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.
Elizabeth J Rivera合作论文数2Helen H Sun合作论文数2Casillas Linda N合作论文数2
Michael A. O'Reilly合作论文数Department of Pediatrics, University of Rochester Medical Center;Department of Environmental Medicine, University of Rochester Medical Center2Mahajan Mukesh K合作论文数2Votta Bart合作论文数2
Peter J. Gough合作论文数Sir William Dunn School of Pathology, University of Oxford2Robert W. Marquis合作论文数Merck Research Laboratories2Rakesh Nagilla合作论文数2Michael N Cook合作论文数1Finger Joshua N合作论文数1DeMartino Michael P合作论文数1Dare Lauren合作论文数1Kristin K. Brown合作论文数1Pamela A. Haile合作论文数1
John D. Lich合作论文数Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center;University of North Carolina;Lineberger Comprehensive Cancer Center, University of North Carolina1Chaya Duraiswami合作论文数Department of Computational and Structural Chemistry, GlaxoSmithKline Pharmaceuticals1
