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Glutathione transferase omega-1 Regulates NLRP3 inflammasome activation through NEK7 deglutathionylation

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journal contribution
posted on 02.07.2021, 09:15 by Mark M Hughes, Alexander Hooftman, Stefano Angiari, Padmaja Tummala, Zbigniew Zaslona, Marah C. Runtsch, Anne F. McGettrick, Caroline E. Sutton, Ciana Diskin, Melissa Rooke, Shuhei Takahashi, Srinivasan Sundararaj, Marco G. Casarotto, Jane E. Dahlstrom, Eva M. Palsson-McDermott, Sinéad C. Corr, Kingston H. G. Mills, Roger PrestonRoger Preston, Nouri Neamati, Yiyue Xie, Jonathan B. Baell, Philip G. Board, Luke AJ O'Neill
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.

Funding

The National Health and Medical Research Council of Australia (NHMRC) Project Grant APP112467

Principal Research Fellowship 1117602

NHMRC Project Grant APP1156455

European Research Council (ECFP7-ERC-MICROINNATE)

Science Foundation Ireland Investigator Award (SFI 12/IA/1531)

History

Comments

The original article is available at https://www.sciencedirect.com/

Published Citation

Hughes MM et al. Glutathione transferase omega-1 regulates NLRP3 inflammasome activation through NEK7 deglutathionylation. Cell Rep. 2019 29(1):151-161.e5.

Publication Date

1 Oct 2019

PubMed ID

31577945

Department/Unit

  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Health Professions Education
  • Vascular Biology

Publisher

Elsevier BV

Version

  • Published Version (Version of Record)