NLRP3NACHT, LRR and PYD domains-containing protein 3

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000250",
          "source": "UniProtKB",
          "id": "Q8R4B8"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "16407889"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
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        {
          "evidenceCode": "ECO:0000269",
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        {
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          "source": "PubMed",
          "id": "18604214"
        },
        {
          "evidenceCode": "ECO:0000269",
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          "id": "19414800"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "22801494"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "23582325"
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        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "23871209"
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        {
          "evidenceCode": "ECO:0000269",
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          "id": "25686105"
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        {
          "evidenceCode": "ECO:0000269",
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        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "27929086"
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        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "28656979"
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        {
          "evidenceCode": "ECO:0000269",
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        {
          "evidenceCode": "ECO:0000269",
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          "id": "31086327"
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          "id": "31086329"
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        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "31189953"
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        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "33231615"
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        {
          "evidenceCode": "ECO:0000269",
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          "id": "34133077"
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        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "34341353"
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        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "34554188"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "35114687"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "36142182"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "36442502"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "39173637"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "40250624"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "40450990"
        }
      ],
      "value": "Sensor component of the NLRP3 inflammasome, which mediates inflammasome activation in response to defects in membrane integrity, leading to secretion of inflammatory cytokines IL1B and IL18 and pyroptosis (PubMed:16407889, PubMed:18403674, PubMed:18604214, PubMed:23582325, PubMed:25686105, PubMed:27929086, PubMed:28656979, PubMed:28847925, PubMed:30487600, PubMed:30612879, PubMed:31086327, PubMed:31086329, PubMed:31189953, PubMed:33231615, PubMed:34133077, PubMed:34341353, PubMed:34512673, PubMed:36442502, PubMed:40250624, PubMed:40450990). In response to pathogens and other damage-associated signals that affect the integrity of membranes, initiates the formation of the inflammasome polymeric complex composed of NLRP3, CASP1 and PYCARD/ASC (PubMed:16407889, PubMed:18403674, PubMed:27432880, PubMed:28847925, PubMed:31189953, PubMed:33231615, PubMed:34133077, PubMed:34341353, PubMed:36142182, PubMed:36442502). Recruitment of pro-caspase-1 (proCASP1) to the NLRP3 inflammasome promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), promoting cytokine secretion and pyroptosis (PubMed:23582325, PubMed:28847925, PubMed:31189953, PubMed:33231615, PubMed:34133077, PubMed:34341353). Activation of NLRP3 inflammasome is also required for HMGB1 secretion; stimulating inflammatory responses (PubMed:22801494). Involved in the homeostatic wound healing response to tissue injury, a multistep cascade that guides neutrophil migration to necrotic sites while avoiding collateral damage of healthy tissues. ATP released from necrotic cells triggers activation of NLRP3 inflammasome through P2RX7 signaling leading to neutrophil adhesion to the vascular endothelium close to the injury site (By similarity). Under resting conditions, ADP-bound NLRP3 is autoinhibited (PubMed:35114687). NLRP3 activation stimuli include extracellular ATP, nigericin, reactive oxygen species, crystals of monosodium urate or cholesterol, amyloid-beta fibers, environmental or industrial particles and nanoparticles, such as asbestos, silica, aluminum salts, cytosolic dsRNA, etc (PubMed:16407889, PubMed:18403674, PubMed:18604214, PubMed:19414800, PubMed:23871209). Almost all stimuli trigger intracellular K(+) efflux (By similarity). These stimuli lead to membrane perturbation and activation of NLRP3 (By similarity). Upon activation, NLRP3 is transported to microtubule organizing center (MTOC), where it is unlocked by NEK7, leading to its relocalization to dispersed trans-Golgi network (dTGN) vesicle membranes and formation of an active inflammasome complex (PubMed:36442502, PubMed:39173637). Associates with dTGN vesicle membranes by binding to phosphatidylinositol 4-phosphate (PtdIns4P) (PubMed:30487600, PubMed:34554188). Shows ATPase activity (PubMed:17483456)"
    }
  ],
  "commentType": "FUNCTION"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000250",
          "source": "UniProtKB",
          "id": "Q8R4B8"
        }
      ],
      "value": "Independently of inflammasome activation, regulates the differentiation of T helper 2 (Th2) cells and has a role in Th2 cell-dependent asthma and tumor growth (By similarity). During Th2 differentiation, required for optimal IRF4 binding to IL4 promoter and for IRF4-dependent IL4 transcription (By similarity). Binds to the consensus DNA sequence 5'-GRRGGNRGAG-3' (By similarity). May also participate in the transcription of IL5, IL13, GATA3, CCR3, CCR4 and MAF (By similarity)"
    }
  ],
  "commentType": "FUNCTION"
}

{
  "commentType": "CATALYTIC ACTIVITY",
  "reaction": {
    "name": "ATP + H2O = ADP + phosphate + H(+)",
    "reactionCrossReferences": [
      {
        "database": "Rhea",
        "id": "RHEA:13065"
      },
      {
        "database": "ChEBI",
        "id": "CHEBI:15377"
      },
      {
        "database": "ChEBI",
        "id": "CHEBI:15378"
      },
      {
        "database": "ChEBI",
        "id": "CHEBI:30616"
      },
      {
        "database": "ChEBI",
        "id": "CHEBI:43474"
      },
      {
        "database": "ChEBI",
        "id": "CHEBI:456216"
      }
    ],
    "evidences": [
      {
        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "17483456"
      },
      {
        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "31086327"
      },
      {
        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "31086329"
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    ]
  },
  "physiologicalReactions": [
    {
      "directionType": "left-to-right",
      "reactionCrossReference": {
        "database": "Rhea",
        "id": "RHEA:13066"
      },
      "evidences": [
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "17483456"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "31086327"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "31086329"
        }
      ]
    }
  ]
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000250",
          "source": "UniProtKB",
          "id": "Q8R4B8"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "16407889"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "18403674"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "18604214"
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        {
          "evidenceCode": "ECO:0000269",
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          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "24008845"
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        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "24630722"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "25686105"
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        {
          "evidenceCode": "ECO:0000269",
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        {
          "evidenceCode": "ECO:0000269",
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        {
          "evidenceCode": "ECO:0000269",
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          "id": "31086327"
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        {
          "evidenceCode": "ECO:0000269",
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          "id": "31086329"
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        {
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          "id": "32843625"
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        {
          "evidenceCode": "ECO:0000269",
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          "id": "33231615"
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        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "34133077"
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        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "34687713"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "35114687"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "35254907"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "35559676"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "36142182"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "36442502"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "39173637"
        }
      ],
      "value": "Under resting conditions, NLRP3 binds ADP and is autoinhibited (PubMed:35114687). Inactive NLRP3 forms homodecameric double-ring cages that hide pyrin domains within NACHT-LRR rings to avoid premature activation (PubMed:35114687). NLRP3 activation stimuli include extracellular ATP, nigericin, reactive oxygen species, crystals of monosodium urate or cholesterol, amyloid-beta fibers, environmental or industrial particles and nanoparticles, such as asbestos, silica, aluminum salts, cytosolic dsRNA, etc (PubMed:16407889, PubMed:18403674, PubMed:18604214, PubMed:19414800, PubMed:35114687). Activated upon human coronavirus SARS-CoV-2 infection (PubMed:33231615, PubMed:34133077). Almost all stimuli trigger intracellular K(+) efflux (By similarity). These stimuli lead to membrane perturbations that induce activation of NLRP3 (By similarity). Upon activation, NLRP3 is transported to microtubule organizing center (MTOC), where it is unlocked by NEK7, leading to its relocalization to dispersed trans-Golgi network (dTGN) vesicle membranes and recruitment of PYCARD/ASC for the formation of an active inflammasome complex (PubMed:30487600, PubMed:30612879, PubMed:36442502, PubMed:39173637). NEK7-activated NLRP3 forms a disk-shaped inflammasome (PubMed:36442502). NLRP3 and PYCARD/ASC interact via their respective pyrin domains; interaction initiates speck formation (nucleation) which greatly enhances further addition of soluble PYCARD/ASC molecules to the speck in a prion-like polymerization process (PubMed:24630722, PubMed:27432880, PubMed:28465465, PubMed:35559676, PubMed:36142182, PubMed:36442502). Clustered PYCARD/ASC nucleates the formation of CASP1 filaments through the interaction of their respective CARD domains, acting as a platform for CASP1 polymerization and activation (PubMed:24630722). Active CASP1 then processes IL1B and IL18 precursors, leading to the release of mature cytokines in the extracellular milieu and inflammatory response (PubMed:24630722). NLRP3 inflammasome assembly is inhibited by IRGM, which impedes NLRP3 oligomerization (PubMed:30612879). NLRP3 inflammasome is activated by cyclic di-AMP (c-di-AMP) and cyclic di-GMP (c-di-GMP), which enhance polymerization (PubMed:24008845). NLRP3 inflammasome is inhibited by cyclic AMP (cAMP), which directly binds NLRP3; inhibition is relieved by calcium-sensing receptor CASR, which inhibits production of cAMP (PubMed:32843625). Specifically inhibited by sulfonylurea MCC950 (also named CP-456,773, CRID3), a potent and specific small-molecule inhibitor of the NLRP3 inflammasome that acts by preventing ATP hydrolysis (PubMed:25686105, PubMed:31086327, PubMed:31086329, PubMed:34687713, PubMed:35114687, PubMed:35254907)"
    }
  ],
  "commentType": "ACTIVITY REGULATION"
}

Eukaryota → Metazoa → Chordata → Craniata → Vertebrata → Euteleostomi → Mammalia → Eutheria → Euarchontoglires → Primates → Haplorrhini → Catarrhini → Hominidae → Homo

{
  "names": {
    "recommendedName": {
      "fullName": {
        "evidences": [
          {
            "evidenceCode": "ECO:0000305"
          }
        ],
        "value": "NACHT, LRR and PYD domains-containing protein 3"
      },
      "ecNumbers": [
        {
          "evidences": [
            {
              "evidenceCode": "ECO:0000269",
              "source": "PubMed",
              "id": "17483456"
            },
            {
              "evidenceCode": "ECO:0000269",
              "source": "PubMed",
              "id": "31086327"
            },
            {
              "evidenceCode": "ECO:0000269",
              "source": "PubMed",
              "id": "31086329"
            }
          ],
          "value": "3.6.4.-"
        }
      ]
    },
    "alternativeNames": [
      {
        "fullName": {
          "value": "Angiotensin/vasopressin receptor AII/AVP-like"
        }
      },
      {
        "fullName": {
          "evidences": [
            {
              "evidenceCode": "ECO:0000303",
              "source": "PubMed",
              "id": "14662828"
            }
          ],
          "value": "Caterpiller protein 1.1"
        },
        "shortNames": [
          {
            "evidences": [
              {
                "evidenceCode": "ECO:0000303",
                "source": "PubMed",
                "id": "14662828"
              }
            ],
            "value": "CLR1.1"
          }
        ]
      },
      {
        "fullName": {
          "evidences": [
            {
              "evidenceCode": "ECO:0000303",
              "source": "PubMed",
              "id": "11687797"
            }
          ],
          "value": "Cold-induced autoinflammatory syndrome 1 protein"
        }
      },
      {
        "fullName": {
          "evidences": [
            {
              "evidenceCode": "ECO:0000303",
              "source": "PubMed",
              "id": "14662828"
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          ],
          "value": "Cryopyrin"
        }
      },
      {
        "fullName": {
          "evidences": [
            {
              "evidenceCode": "ECO:0000303",
              "source": "PubMed",
              "id": "11786556"
            }
          ],
          "value": "PYRIN-containing APAF1-like protein 1"
        }
      }
    ]
  },
  "genes": [
    {
      "geneName": {
        "evidences": [
          {
            "evidenceCode": "ECO:0000303",
            "source": "PubMed",
            "id": "17907925"
          },
          {
            "evidenceCode": "ECO:0000312",
            "source": "HGNC",
            "id": "HGNC:16400"
          }
        ],
        "value": "NLRP3"
      },
      "synonyms": [
        {
          "evidences": [
            {
              "evidenceCode": "ECO:0000312",
              "source": "HGNC",
              "id": "HGNC:16400"
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          ],
          "value": "C1orf7"
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        {
          "evidences": [
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              "evidenceCode": "ECO:0000303",
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          ],
          "value": "CIAS1"
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        {
          "evidences": [
            {
              "evidenceCode": "ECO:0000303",
              "source": "PubMed",
              "id": "12355493"
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          ],
          "value": "NALP3"
        },
        {
          "evidences": [
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              "evidenceCode": "ECO:0000303",
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              "id": "11786556"
            }
          ],
          "value": "PYPAF1"
        }
      ]
    }
  ]
}

{
  "commentType": "DISEASE",
  "disease": {
    "diseaseId": "Familial cold autoinflammatory syndrome 1",
    "diseaseAccession": "DI-01561",
    "acronym": "FCAS1",
    "description": "A rare autosomal dominant systemic inflammatory disease characterized by recurrent episodes of maculopapular rash associated with arthralgias, myalgias, fever and chills, swelling of the extremities, and conjunctivitis after generalized exposure to cold. Rarely, some patients may also develop late-onset renal amyloidosis.",
    "diseaseCrossReference": {
      "database": "MIM",
      "id": "120100"
    },
    "evidences": [
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        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
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        "source": "PubMed",
        "id": "11992256"
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      {
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        "source": "PubMed",
        "id": "12355493"
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      {
        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "12522564"
      },
      {
        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "15593220"
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      {
        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "17284928"
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        "source": "PubMed",
        "id": "24952504"
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    ]
  },
  "note": {
    "texts": [
      {
        "value": "The disease is caused by variants affecting the gene represented in this entry"
      }
    ]
  }
}

{
  "commentType": "DISEASE",
  "disease": {
    "diseaseId": "Muckle-Wells syndrome",
    "diseaseAccession": "DI-00783",
    "acronym": "MWS",
    "description": "A hereditary periodic fever syndrome characterized by fever, chronic recurrent urticaria, arthralgias, progressive sensorineural deafness, and reactive renal amyloidosis. The disease may be severe if generalized reactive amyloidosis occurs.",
    "diseaseCrossReference": {
      "database": "MIM",
      "id": "191900"
    },
    "evidences": [
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        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "11687797"
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      {
        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "11992256"
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        "id": "12355493"
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      {
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        "source": "PubMed",
        "id": "15593220"
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        "source": "PubMed",
        "id": "24952504"
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    ]
  },
  "note": {
    "texts": [
      {
        "value": "The disease is caused by variants affecting the gene represented in this entry"
      }
    ]
  }
}

{
  "commentType": "DISEASE",
  "disease": {
    "diseaseId": "Chronic infantile neurologic cutaneous and articular syndrome",
    "diseaseAccession": "DI-01349",
    "acronym": "CINCA",
    "description": "Rare congenital inflammatory disorder characterized by a triad of neonatal onset of cutaneous symptoms, chronic meningitis, and joint manifestations with recurrent fever and inflammation.",
    "diseaseCrossReference": {
      "database": "MIM",
      "id": "607115"
    },
    "evidences": [
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        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "12032915"
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      {
        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "12483741"
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      {
        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "14630794"
      },
      {
        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "15231984"
      },
      {
        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "15334500"
      },
      {
        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "15593220"
      },
      {
        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "24952504"
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        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "31086329"
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    ]
  },
  "note": {
    "texts": [
      {
        "value": "The disease is caused by variants affecting the gene represented in this entry"
      }
    ]
  }
}

{
  "commentType": "DISEASE",
  "disease": {
    "diseaseId": "Keratoendothelitis fugax hereditaria",
    "diseaseAccession": "DI-05200",
    "acronym": "KEFH",
    "description": "An autosomal dominant corneal disease that periodically, and fleetingly, affects the corneal endothelium, stroma, and vision, eventually leading to central corneal stromal opacities in some patients. The disease is characterized by unilateral attacks of ocular pain, pericorneal injection, and photophobia. The acute symptoms vanish in 1-2 days but vision remains blurry for several weeks. The attacks start at the age of 3-12 years and can affect either eye. They generally decrease in frequency and get milder with age.",
    "diseaseCrossReference": {
      "database": "MIM",
      "id": "148200"
    },
    "evidences": [
      {
        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "29366613"
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        "source": "PubMed",
        "id": "35559676"
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    ]
  },
  "note": {
    "texts": [
      {
        "value": "The disease is caused by variants affecting the gene represented in this entry"
      }
    ]
  }
}

{
  "commentType": "DISEASE",
  "disease": {
    "diseaseId": "Deafness, autosomal dominant, 34, with or without inflammation",
    "diseaseAccession": "DI-05146",
    "acronym": "DFNA34",
    "description": "A form of sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA34 is a postlingual, slowly progressive form with variable severity and variable additional features. Some DFNA34 patients have autoinflammatory manifestations.",
    "diseaseCrossReference": {
      "database": "MIM",
      "id": "617772"
    },
    "evidences": [
      {
        "evidenceCode": "ECO:0000269",
        "source": "PubMed",
        "id": "28847925"
      }
    ]
  },
  "note": {
    "texts": [
      {
        "value": "The disease may be caused by variants affecting the gene represented in this entry"
      }
    ]
  }
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000250",
          "source": "UniProtKB",
          "id": "Q8R4B8"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "24623131"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "27043286"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "28465465"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "28943315"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "34554188"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "34615873"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "39173637"
        }
      ],
      "value": "Phosphorylation at Ser-198 by MAPK8/JNK1 increases inflammasome activation by promoting deubiquitination by BRCC3 and NLRP3 homooligomerization (PubMed:28943315). Phosphorylation at Ser-806 by CSNK1A1 prevents inflammasome activation by preventing NEK7 recruitment (PubMed:34615873). Phosphorylation at Ser-5 in the pyrin domain inhibits homomultimerization of NLRP3 and activation of the NLRP3 inflammasome: dephosphorylation by protein phosphatase 2A (PP2A) promotes assembly of the NLRP3 inflammasome (PubMed:28465465). Phosphorylation at Ser-295 by PKD/PRKD1 promotes NLRP3 inflammasome assembly (By similarity). Phosphorylation by ERK1/MAPK3 promotes NLRP3 inflammasome assembly (PubMed:24623131). Phosphorylation by BTK (at Tyr-136, Tyr-140, Tyr-143 and Tyr-168) in the region that mediates binding to phosphatidylinositol phosphate, promotes relocalization of NLRP3 and assembly of the NLRP3 inflammasome (PubMed:34554188). Phosphorylation at Tyr-861 inhibits NLRP3 inflammasome assembly: dephosphorylation by PTPN22 promotes inflammasome activation (PubMed:27043286). Phosphorylated by LATS1 and LATS2 at Ser-265 following palmitoylation by ZDHHC1, promoting its relocalization to the microtubule organizing center (MTOC), where NLRP3 is activated by NEK7, leading to inflammasome assembly and activation (PubMed:39173637)"
    }
  ],
  "commentType": "PTM"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000250",
          "source": "UniProtKB",
          "id": "Q8R4B8"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "22948162"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "26037928"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "27929086"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "34512673"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "37575012"
        }
      ],
      "value": "Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination (PubMed:22948162, PubMed:27929086). Ubiquitination does not lead to degradation, but inhibits inflammasome activation (By similarity). Deubiquitination is catalyzed by BRCC3 and associated with NLRP3 activation and inflammasome assembly (By similarity). This process can be induced by the activation of Toll-like receptors (by LPS), through a non-transcriptional pathway dependent on the mitochondrial production of reactive oxygen species, and by ATP (By similarity). Ubiquitinated by TRIM31 via 'Lys-48'-linked ubiquitination, leading to its degradation by the proteasome (PubMed:27929086). Ubiquitinated at Lys-689 by the SCF(FBXL2) complex, leading to its degradation by the proteasome (PubMed:26037928). Ubiquitinated by TRIM35 via 'lys-48' and 'Lys-63'-linked ubiquitination leading to inhibition of NLRP3 inflammasome activation (PubMed:34512673). Undergoes 'Lys-27'-linked polyubiquitination by MARCHF5, leading to NLRP3-NEK7 complex formation and NLRP3 oligomerization (PubMed:37575012)"
    }
  ],
  "commentType": "PTM"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "36586411"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "38092000"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "39173637"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "39225180"
        }
      ],
      "value": "Palmitoylation by ZDHHC12 promotes NLRP3 degradation by the chaperone-mediated autophagy pathway (CMA) and therefore limits NLRP3 inflammasome activation (PubMed:36586411, PubMed:39225180). Following palmitoylation, HSPA8/HSC70 recognizes and binds the KFERQ-like motifs on NLRP3 and promotes NLRP3 recruitment to lysosomes, where it is degraded via the chaperone-mediated autophagy pathway in a LAMP2-dependent process (PubMed:36586411). Palmitoylation at Cys-837 and Cys-838 by ZDHHC5 enhances its binding to NEK7 leading to inflammasome assembly and activation (PubMed:38092000). Palmitoylation at Cys-130 and Cys-958 by ZDHHC1 facilitates phosphorylation at Ser-265 by LATS1 and LATS2, promoting its relocalization to the microtubule organizing center (MTOC), where NLRP3 is activated by NEK7, leading to inflammasome assembly and activation (PubMed:39173637). Depalmitoylated by ABHD17A (PubMed:38092000)"
    }
  ],
  "commentType": "PTM"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "30612879"
        }
      ],
      "value": "Degraded via selective autophagy following interaction with IRGM (PubMed:30612879). IRGM promotes NLRP3 recruitment to autophagosome membranes, promoting its SQSTM1/p62-dependent autophagy-dependent degradation (PubMed:30612879)"
    }
  ],
  "commentType": "PTM"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000305",
          "source": "PubMed",
          "id": "21880711"
        }
      ],
      "value": "The disulfide bond in the pyrin domain might play a role in reactive oxygen species-mediated activation"
    }
  ],
  "commentType": "PTM"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "25538194"
        }
      ],
      "value": "(Microbial infection) ADP-ribosylated by M.pneumoniae CARDS toxin in vitro"
    }
  ],
  "commentType": "PTM"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "11786556"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "12032915"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "17164409"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "17907925"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "23229815"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "33231615"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "34133077"
        }
      ],
      "value": "Predominantly expressed in macrophages (PubMed:33231615, PubMed:34133077). Also expressed in dendritic cells, B- and T-cells (at protein level) (PubMed:11786556, PubMed:17164409). Expressed in LPS-treated granulocytes, but not in resting cells (at protein level) (PubMed:17164409). Expression in monocytes is very weak (at protein level) (PubMed:17164409). Expressed in stratified non-keratinizing squamous epithelium, including oral, esophageal and ectocervical mucosa and in the Hassall's corpuscles in the thymus. Also, detected in the stratified epithelium covering the bladder and ureter (transitional mucosa) (at protein level) (PubMed:17164409). Expressed in lung epithelial cells (at protein level) (PubMed:23229815). Expressed in chondrocytes (PubMed:12032915). Expressed at low levels in resting osteoblasts (PubMed:17907925)"
    }
  ],
  "commentType": "TISSUE SPECIFICITY"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "14662828"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "17907925"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "23955712"
        }
      ],
      "value": "By activators of Toll-like receptors, such as lipoteichoic acid (LTA) (TLR2), polyinosine-polycytidylic acid (poly(I:C), a synthetic analog of dsRNA) (TLR3) and bacterial lipopolysaccharides (LPS) (TLR4), and by TNF (PubMed:14662828). Up-regulated in osteoblasts after exposure to invasive, but not invasion-defective, strains of Salmonella typhimurium (at protein level) (PubMed:17907925). In macrophages, up-regulated by endocannabinoid anandamide/AEA (PubMed:23955712)"
    }
  ],
  "commentType": "INDUCTION"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "34133077"
        }
      ],
      "value": "(Microbial infection) In COVID-19 patient derived macrophages, expression is induced by SARS-CoV-2 spike protein, probably via TLR2 (at protein level)"
    }
  ],
  "commentType": "INDUCTION"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000250",
          "source": "UniProtKB",
          "id": "Q8R4B8"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "11786556"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "15030775"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "17431422"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "21880711"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "22461501"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "22801494"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "23430110"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "23582325"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "23809162"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "23871209"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "24517500"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "24531343"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "26347139"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "27432880"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "28656979"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "30612879"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "31189953"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "34341353"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "35114687"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "35254907"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "35559676"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "36142182"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "36442502"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "36586411"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "37575012"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "38092000"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "39173637"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "39225180"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "39333773"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "40250624"
        }
      ],
      "value": "Sensor component of NLRP3 inflammasomes; inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation (PubMed:11786556, PubMed:15030775, PubMed:21880711). The core of NLRP3 inflammasomes consists of a signal sensor component (NLRP3), an adapter (PYCARD/ASC), which recruits an effector pro-inflammatory caspase (CASP1 and, possibly, CASP4 and CASP5) (PubMed:11786556, PubMed:15030775, PubMed:21880711). Homodecamer; inactive NLRP3 forms homodecameric double-ring cages that hide pyrin domains within NACHT-LRR rings to avoid premature activation (PubMed:35114687, PubMed:35254907). Interacts (via pyrin domain) with PYCARD/ASC (via pyrin domain); interaction is direct (PubMed:11786556, PubMed:27432880, PubMed:34341353, PubMed:35559676, PubMed:36142182, PubMed:36442502). Interacts (via LRR repeat domain) with NEK7 (via N-terminus); the interaction is required for the formation of the complex NLRP3:PYCARD, oligomerization of PYCARD/ASC and activation of CASP1 (PubMed:31189953, PubMed:36442502, PubMed:38092000, PubMed:39173637, PubMed:37575012). Interacts (via LRR repeat domain) with NR4A1/Nur77 (via N-terminus); the interaction is direct, requires activation of NR4A1 by its ligands NBRE-containing dsDNA and lipopolysaccharide, and stimulates the association of NLRP3 with NEK7 for non-canonical NLRP3 inflammasome activation (By similarity). Interacts with CARD8; leading to inhibit formation of the NLRP3 inflammasome (PubMed:24517500). Interacts with MEFV; this interaction targets NLRP3 to degradation by autophagy, hence preventing excessive IL1B- and IL18-mediated inflammation (PubMed:17431422, PubMed:26347139). Interacts with EIF2AK2/PKR; this interaction requires EIF2AK2 activity, is accompanied by EIF2AK2 autophosphorylation and promotes inflammasome assembly in response to specific stimuli (PubMed:22801494). Interacts with GBP5 (via DAPIN domain); this interaction promotes inflammasome assembly in response to microbial and soluble, but not crystalline, agents (PubMed:22461501). Interacts with PML (isoform PML-1) (via the leucine-rich repeat (LRR) domain); PML-mediated increase in NLRP3 inflammasome activation does not depend upon this interaction (PubMed:23430110). Interacts (via NACHT domain) with DHX33 (via DEAH box); NLRP3 activation in presence of cytosolic dsRNA is mediated by DHX33 (PubMed:23871209). Interacts (via NACHT and LRR domains) with ARRB2; this interaction is direct and inducible by polyunsaturated fatty acids (PUFAs) (PubMed:23809162). Interacts with PYDC5 (PubMed:24531343). Interacts (via NACHT domain) with DDX3X under both LPS-primed and inflammasome-activating conditions (By similarity). Interacts with IRF4 (via the LRR domain); this interaction is direct and is required for optimal IRF4 binding to IL4 promoter and efficient IL4 transactivation during differentiation of Th2 helper T cells (By similarity). Interacts with MAVS; promoting localization to mitochondria and activation of the NLRP3 inflammasome (PubMed:23582325). Interacts with MARK4; promoting localization of NLRP3 to the microtubule organizing center (MTOC) (PubMed:28656979). Interacts with TRIM50; this interaction also promotes NLRP3 oligomerization and subsequent inflammasome activation (By similarity). Interacts with IRGM; preventing NLRP3 inflammasome assembly and promoting NLRP3 degradation (PubMed:30612879). Interacts (via KFERQ-like motifs) with HSPA8/HSC70; promoting NLRP3 degradation by the chaperone-mediated autophagy pathway (PubMed:36586411). Interacts (via NACHT and LLR domains) with ABHD8; this interaction is enhanced in the presence of NLRP3 inflammasome inducers, such as ATP, nigericin, silica, or alum. Interaction with ABHD8 leads the recruitment of ZDHHC12, hence facilitating NLRP3 palmitoylation and degradation by the chaperone-mediated autophagy pathway (CMA), therefore attenuating NLRP3 inflammasome activation (PubMed:39225180). Interacts with ZNFX1; the interaction inhibits NLRP3 inflammasome activation by sequestering NLRP3 in the cytoplasm (PubMed:39333773). Interacts with FAM120A; this interaction inhibits inflammasome activation (PubMed:40250624)"
    }
  ],
  "commentType": "SUBUNIT"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "34341353"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "39225180"
        }
      ],
      "value": "(Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 N protein; the interaction is direct and promotes the binding of NLRP3 with PYCARD/ASC and facilitates NLRP3 inflammasome assembly (PubMed:34341353). This interaction disrupts the association between NLRP3 and ABHD8, enhancing NLRP3 stability, ultimately leading to increased inflammasome activation (PubMed:39225180)"
    }
  ],
  "commentType": "SUBUNIT"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "25538194"
        }
      ],
      "value": "(Microbial infection) Interacts with M.pneumoniae CARDS toxin, which ADP-ribosylates NLRP3"
    }
  ],
  "commentType": "SUBUNIT"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "40450990"
        }
      ],
      "value": "(Microbial infection) Interacts with human cytomegalovirus protein US18; this interaction promotes inflammasome assembly"
    }
  ],
  "commentType": "SUBUNIT"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "24630722"
        }
      ],
      "value": "The pyrin domain (also called DAPIN domain or PYD) is involved in PYCARD/ASC-binding"
    }
  ],
  "commentType": "DOMAIN"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "34524838"
        },
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "36442502"
        }
      ],
      "value": "The FISNA domain is a critical mediator of NLRP3 conformational during NLRP3 activation (PubMed:34524838, PubMed:36442502). It becomes ordered in its key regions during activation to stabilize the active NACHT conformation and mediate most interactions in the NLRP3 disk (PubMed:36442502)"
    }
  ],
  "commentType": "DOMAIN"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "23430110"
        }
      ],
      "value": "The LRR domain mediates the interaction with IRF4, PML, NEK7 and NR4A1/Nur77"
    }
  ],
  "commentType": "DOMAIN"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000269",
          "source": "PubMed",
          "id": "36586411"
        }
      ],
      "value": "The KFERQ-like motifs mediate binding to HSPA8/HSC70 following NLRP3 paylmitoylation by ZDHHC12"
    }
  ],
  "commentType": "DOMAIN"
}

{
  "texts": [
    {
      "evidences": [
        {
          "evidenceCode": "ECO:0000305"
        }
      ],
      "value": "Belongs to the NLRP family"
    }
  ],
  "commentType": "SIMILARITY"
}