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Cell Rep. 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.

Author information

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.

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

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