Year: 2022
Type: article
Abstract: At least six human proteins detect danger-associated signals, assemble into complexes called inflammasomes, and trigger pyroptotic cell death. NLRP1 was the first protein discovered to form an inflammasome, but the danger signals and molecular mechanisms that control its activation have not yet been fully established. Here, we report that the NACHT-LRR region of NLRP1 directly binds to oxidized form of thioredoxin-1 (TRX1). We found that NLRP1 requires the ATPase activity of its NACHT domain to associate with TRX1, and that this interaction represses inflammasome activation. Moreover, we discovered that several patient-derived missense mutations in the NACHT-LRR region of NLRP1 weaken TRX1 binding, leading to inflammasome hyperactivation and autoinflammatory disease. Overall, our results establish that oxidized TRX1 binds to and restrains the NLRP1 inflammasome, thereby revealing a link between the cellular redox environment and innate immunity.
Source: Science Immunology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1146059499, G2051006376, Characterizing the DPP8/9 Pyroptotic Checkpoint with Chemoproteomic Protease Substrate Profiling, G2695487608, G289723095, G4165928844, G9000003249, G9000023522, G9000075219, G9000224218, G9000275082, Cancer Center Support Grant, Characterizing the Mechanism of DPP8/9 Inhibitor-Induced Pyroptosis, Prolidase Inhibitors as Therapeutic Agents for Acute Myeloid Leukemia, Tri-institutional PhD Program in Chemical Biology
OpenAlex ID: W4308338215