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. 2019 Oct 1;29(1):151-161.e5.
doi: 10.1016/j.celrep.2019.08.072.

Glutathione Transferase Omega-1 Regulates NLRP3 Inflammasome Activation through NEK7 Deglutathionylation

Mark M Hughes  1 , Alexander Hooftman  2 , Stefano Angiari  2 , Padmaja Tummala  3 , Zbigniew Zaslona  2 , Marah C Runtsch  2 , Anne F McGettrick  2 , Caroline E Sutton  2 , Ciana Diskin  2 , Melissa Rooke  3 , Shuhei Takahashi  4 , Srinivasan Sundararaj  3 , Marco G Casarotto  3 , Jane E Dahlstrom  5 , Eva M Palsson-McDermott  2 , Sinead C Corr  6 , Kingston H G Mills  2 , Roger J S Preston  7 , Nouri Neamati  8 , Yiyue Xie  9 , Jonathan B Baell  9 , Philip G Board  3 , Luke A J O'Neill  10
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Free article

Glutathione Transferase Omega-1 Regulates NLRP3 Inflammasome Activation through NEK7 Deglutathionylation

Mark M Hughes et al. Cell Rep. .
Free article

Abstract

The NLRP3 inflammasome is a cytosolic complex sensing phagocytosed material and various damage-associated molecular patterns, triggering production of the pro-inflammatory cytokines interleukin-1 beta (IL)-1β and IL-18 and promoting pyroptosis. Here, we characterize glutathione transferase omega 1-1 (GSTO1-1), a constitutive deglutathionylating enzyme, as a regulator of the NLRP3 inflammasome. Using a small molecule inhibitor of GSTO1-1 termed C1-27, endogenous GSTO1-1 knockdown, and GSTO1-1-/- mice, we report that GSTO1-1 is involved in NLRP3 inflammasome activation. Mechanistically, GSTO1-1 deglutathionylates cysteine 253 in NIMA related kinase 7 (NEK7) to promote NLRP3 activation. We therefore identify GSTO1-1 as an NLRP3 inflammasome regulator, which has potential as a drug target to limit NLRP3-mediated inflammation.

Keywords: GSTO1-1; IL-1β; NEK7; NLRP3 inflammasome; deglutathionylation; glutathione; pyroptosis.

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