Thioredoxin-1 inhibits NLRP1 inflammasomes

Inflammasomes are a multi-protein cytoplasmic complex that senses danger signals
.
NLRP1 inflammasomes can be experimentally activated by a variety of
stimuli, but the core endogenous red flags that trigger NLPR1 activation remain elusive.
Using proteomics methods to identify proteins that bind to the N-terminal regulatory region of human NLRP1, the researchers found that NLRP1 activation is typically inhibited
by binding to oxidized thiorioreddin-1 (TRX1).
Under cellular conditions where reactive oxygen species are in short supply, a decrease in oxidized TRX1 leads to an increase
in NLRP1 activity.
The findings provide new insights into all cellular parameters that the innate immune system is able to sense, as it investigates unwelcome red flags
in the intracellular environment.

Red flags for activation of NLRP1 inflammasomes have not been established
.
Here, we report the binding of oxidized thiorioredoxin-1 (TRX1) to NLRP1, and we found that the NACHT-LRR region of oxidized TRX1 binds to NLRP1 during ATP-dependent processes, forming a stable complex that inhibits the activation
of inflamators.
Consistent with these findings, in the NACHT-LRR region, patient-derived and ATPase inactivated mutations lead to overactive inflammasome formation that interferes with TRX1 binding
.
Overall, this work strongly suggests that reducing stress is a red flag that eliminates oxidized TRX1 and eliminates TRX1-NLRP1 interactions, a red flag
for activating the NLRP1 inflamator.