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

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; Sinead C Corr; Kingston H G Mills; Roger J S Preston; Nouri Neamati; Yiyue Xie; Jonathan B Baell; Philip G Board; Luke A J O'Neill

doi:10.1016/j.celrep.2019.08.072

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

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

Authors

Mark M Hughes¹, Alexander Hooftman², Stefano Angiari², Padmaja Tummala³, Zbigniew Zaslona², Marah C Runtsch², Anne F McGettrick², Caroline E Sutton², Ciana Diskin², Melissa Rooke³, Shuhei Takahashi⁴, Srinivasan Sundararaj³, Marco G Casarotto³, Jane E Dahlstrom⁵, Eva M Palsson-McDermott², Sinead C Corr⁶, Kingston H G Mills², Roger J S Preston⁷, Nouri Neamati⁸, Yiyue Xie⁹, Jonathan B Baell⁹, Philip G Board³, Luke A J O'Neill¹⁰

Affiliations

¹ School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
² School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
³ John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.
⁴ Department of Human Pathology, Graduate School and Faculty of Medicine, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
⁵ ACT Pathology and ANU Medical School, The Canberra Hospital, Canberra, ACT, Australia.
⁶ Department of Microbiology, Moyne Institute of Preventive Medicine, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland.
⁷ Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
⁸ Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, USA; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, MI 48109, USA; Translational Oncology Program, University of Michigan, 2800 Plymouth Road, Building 520, Room 1363, Ann Arbor, MI 48109, USA.
⁹ Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
¹⁰ School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: laoneill@tcd.ie.

PMID: 31577945
DOI: 10.1016/j.celrep.2019.08.072

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.

MeSH terms

Animals
Cytokines / metabolism
Glutathione Transferase / metabolism*
HEK293 Cells
Humans
Inflammasomes / metabolism*
Inflammation / metabolism
Inflammation Mediators / metabolism
Mice
Mice, Inbred C57BL
NIMA-Related Kinases / metabolism*
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*

Substances

Cytokines
Inflammasomes
Inflammation Mediators
NLR Family, Pyrin Domain-Containing 3 Protein
NLRP3 protein, human
GSTO1 protein, human
Glutathione Transferase
NEK7 protein, human
NIMA-Related Kinases