Autolytic proteolysis within the function to find domain (FIIND) is required for NLRP1 inflammasome activity.
Nucleotide-binding domain leucine-rich repeat proteins (NLRs) play a key role in immunity and disease through their ability to modulate inflammation in response to pathogen-derived and endogenous danger signals. Here, we identify the requirements for activation of NLRP1, an NLR protein associated with a number of human pathologies, including vitiligo, rheumatoid arthritis, and Crohn disease. We demonstrate that NLRP1 activity is dependent upon ASC, which associates with the C-terminal CARD domain of NLRP1. In addition, we show that NLRP1 activity is dependent upon autolytic cleavage at Ser(1213) within the FIIND. Importantly, this post translational event is dependent upon the highly conserved distal residue His(1186). A disease-associated single nucleotide polymorphism near His(1186) and a naturally occurring mRNA splice variant lacking exon 14 differentially affect this autolytic processing and subsequent NLRP1 activity. These results describe key molecular pathways that regulate NLRP1 activity and offer insight on how small sequence variations in NLR genes may influence human disease pathogenesis.
Pattern Recognition Receptor Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.
Joshua N
JN
Finger
John D
JD
Lich
Lauren C
LC
Dare
Michael N
MN
Cook
Kristin K
KK
Brown
Chaya
C
Duraiswami
John
J
Bertin
John J
JJ
Bertin
Peter J
PJ
Gough
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D000070576:NLR Proteins; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000276:immunology*; D017434:Protein Structure, Tertiary; D059748:Proteolysis
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D058847:Inflammasomes; D000070576:NLR Proteins; C427903:NLRP1 protein, human