Cryo-EM structure of NLRP1-DPP9-VbP complex

Acts as the sensor component of the NLRP1 inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis ^[1–10]. 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 ^{[1, 2, 3]}. Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, such as cleavage by some human enteroviruses and rhinoviruses, double-stranded RNA, UV-B irradiation, or Val-boroPro inhibitor, and mediates the formation of the inflammasome polymeric complex composed of NLRP1, CASP1 and PYCARD/ASC ^{[1, 2, 3, 11, 12, 13, 6, 14, 7, 10]}.

In response to pathogen-associated signals, the N-terminal part of NLRP1 is degraded by the proteasome, releasing the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1, C-terminus), which polymerizes and associates with PYCARD/ASC to initiate the formation of the inflammasome complex: the NLRP1 inflammasome recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), leading to pyroptosis ^{[1, 2, 3, 15, 6]}. In the absence of GSDMD expression, the NLRP1 inflammasome is able to recruit and activate CASP8, leading to activation of gasdermin-E (GSDME) ^{[16, 17]}. Activation of NLRP1 inflammasome is also required for HMGB1 secretion; the active cytokines and HMGB1 stimulate inflammatory responses ^[18].

Binds ATP and shows ATPase activity ^{[19, 20, 14]}. Plays an important role in antiviral immunity and inflammation in the human airway epithelium ^[6]. Specifically recognizes a number of pathogen-associated signals: upon infection by human rhinoviruses 14 and 16 (HRV-14 and HRV-16), NLRP1 is cleaved and activated which triggers NLRP1-dependent inflammasome activation and IL18 secretion ^[6].

Positive-strand RNA viruses, such as Semliki forest virus and long dsRNA activate the NLRP1 inflammasome, triggering IL1B release in a NLRP1-dependent fashion ^[14]. Acts as a direct sensor for long dsRNA and thus RNA virus infection ^[14]. May also be activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, in a NOD2-dependent manner ^[21].

The NLRP1 inflammasome is also activated in response to UV-B irradiation causing ribosome collisions: ribosome collisions cause phosphorylation and activation of NLRP1 in a MAP3K20-dependent manner, leading to pyroptosis ^[10] Constitutes the precursor of the NLRP1 inflammasome, which mediates autoproteolytic processing within the FIIND domain to generate the N-terminal and C-terminal parts, which are associated non-covalently in absence of pathogens and other damage-associated signals Regulatory part that prevents formation of the NLRP1 inflammasome: in absence of pathogens and other damage-associated signals, interacts with the C-terminal part of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus), preventing activation of the NLRP1 inflammasome ^[6]. In response to pathogen-associated signals, this part is ubiquitinated and degraded by the proteasome, releasing the cleaved C-terminal part of the protein, which polymerizes and forms the NLRP1 inflammasome ^[6] Constitutes the active part of the NLRP1 inflammasome ^{[6, 8, 9]}. In absence of pathogens and other damage-associated signals, interacts with the N-terminal part of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, N-terminus), preventing activation of the NLRP1 inflammasome ^[6].

In response to pathogen-associated signals, the N-terminal part of NLRP1 is degraded by the proteasome, releasing this form, which polymerizes and associates with PYCARD/ASC to form of the NLRP1 inflammasome complex: the NLRP1 inflammasome complex then directly recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, leading to gasdermin-D (GSDMD) cleavage and subsequent pyroptosis ^[6] It is unclear whether is involved in inflammasome formation. It is not cleaved within the FIIND domain, does not assemble into specks, nor promote IL1B release ^[3]. However, in an vitro cell-free system, it has been shown to be activated by MDP ^[2]