No abstract

The danger signals that activate the NLRP1 inflammasome have not been established. Here, we report that the oxidized, but not the reduced, form of thioredoxin-1 (TRX1) binds to NLRP1. We found that oxidized TRX1 associates with the NACHT-LRR region of NLRP1 in an ATP-dependent process, forming a stable complex that restrains inflammasome activation. Consistent with these findings, patient-derived and ATPase-inactivating mutations in the NACHT-LRR region that cause hyperactive inflammasome formation interfere with TRX1 binding. Overall, this work strongly suggests that reductive stress, the cellular perturbation that will eliminate oxidized TRX1 and abrogate the TRX1-NLRP1 interaction, is a danger signal that activates the NLRP1 inflammasome.

Pacific salmon Oncorhynchus spp. experience multiple small‐scale disturbances throughout their freshwater habitat, but the cumulative effect of these disturbances is often not known or not easily quantifiable. One such disturbance is water diversions, which can entrain fish and alter streamflow regimes. Threatened Lemhi River (Idaho) Chinook salmon O. tshawytscha smolts encounter 41–71 water diversions during their out‐migration. We used passive integrated transponder tag data to model the entrainment rate of Chinook salmon smolts as a function of the proportion of water removed by an irrigation diversion. Under median‐streamflow conditions with unscreened diversions, the estimated cumulative effect of the diversions was a loss of 71.1% of out‐migrating smolts due to entrainment. This is a large potential source of mortality, but screening is an effective mitigation strategy, as estimated mortality was reduced to 1.9% when all diversions were screened. If resources are limited, targeting the diversions that remove a large amount of water and diversions in locations with high fish encounter rates is most effective. Our modeling approach could be used to quantify the entrainment effects of water diversions and set screening priorities for other watersheds.

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.