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Oxidized thioredoxin-1 restrains the NLRP1 inflammasome [mBMDM]

UID: 11167

Author(s): Ball, Daniel*, Bachovchin, Daniel* * MSK affiliated

Description
Summary from GEO:

"The danger signals that activate the NLRP1 inflammasome have yet to be firmly established. NLRP1 undergoes autoproteolysis to generate N-terminal (NT) and C-terminal (CT) fragment, which importantly, is a necessary step for its check-point regulation by the DPP9 ternary complex and the mechanistic activation of NLRP1 through functional degradation. Here, we report an added layer of regulatory complexity to NLRP1 activity, in the form of a repressive interaction that NLRP1 forms with the oxidized, but not reduced, form of thioredoxin-1 (TRX1). Loss of TRX1 destabilizes the NT fragment of NLRP1 and promotes enhanced inflammasome activation. The TRX1 interaction occurs through the NACHT-LRR of NLRP1 and requires nucleotide binding in its ATPase domain. In addition, we found that several patient-derived and ATPase-inactivating mutations in the NACHT-LRR region hyperactive the inflammasome by destabilize protein folding and are also shown to abrogate TRX1 binding. Thus, NLRP1 appears to detect intracellular reductive stress through a decrease in the fraction of intracellular oxidized TRX1, which enhances protein disorder, leading to inflammasome signaling. These findings link the cellular redox environment to NLRP1-mediated innate immunity."

Overall design from GEO:

"Total RNA content from wild-type and Txn1 KO C57BL/6J mouse BMDMs is analyzed by RNASeq. Experiment was performed in triplicate, and the differential gene expression analysis was used to determine the impact of TRX1 protein loss on the expression of NLRP1 inflammasome genes."
Subject of Study
Mus musculus
Subject(s)
Gene Expression
Inflammasomes
Protein Folding
RNA-Seq
Thioredoxins
Access via GEO


Accession #: GSE215035

Access via BioProject


Accession #: PRJNA888114

Access Restrictions
Free to All
Access Instructions
The NCBI Gene Expression Omnibus and BioProject databases provide open access to these files.
Associated Publications
Ball D, Tsamouri L, Wang A, Huang H, Warren C, Wang Q, Edmondson I, Griswold A, Rao S, Johnson D, Bachovchin D. Oxidized thioredoxin-1 restrains the NLRP1 inflammasome. Science Immunology. 2022; 7(77):eabm7200.
Equipment Used
Illumina HiSeq 4000

High throughput gene sequencing system

Dataset Format(s)
CSV
Dataset Size
1.1 MB
Data Catalog Record Updated
2024-02-21