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
Affiliations
Mark M. Hughes
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
Alexander Hooftman
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Stefano Angiari
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Padmaja Tummala
John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia
Zbigniew Zaslona
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Marah C. Runtsch
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Anne F. McGettrick
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Caroline E. Sutton
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Ciana Diskin
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Melissa Rooke
John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia
Shuhei Takahashi
Department of Human Pathology, Graduate School and Faculty of Medicine, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Srinivasan Sundararaj
John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia
Marco G. Casarotto
John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia
Jane E. Dahlstrom
ACT Pathology and ANU Medical School, The Canberra Hospital, Canberra, ACT, Australia
Eva M. Palsson-McDermott
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Sinead C. Corr
Department of Microbiology, Moyne Institute of Preventive Medicine, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland
Kingston H.G. Mills
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Roger J.S. Preston
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
Nouri Neamati
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
Yiyue Xie
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Jonathan B. Baell
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Philip G. Board
John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia
Luke A.J. O’Neill
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; Corresponding author
Summary: 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. : NLRP3 inflammasome activation contributes to chronic inflammation associated with autoinflammatory disease, yet understanding of NLRP3 inflammasome regulation is incomplete. Hughes et al. show that the deglutathionylating enzyme GSTO1-1 promotes NLRP3 inflammasome activation through deglutathionylation of NEK7. Furthermore, the GSTO1-1 inhibitor C1-27 reduces NLRP3 inflammasome activation in vitro and in vivo. Keywords: NLRP3 inflammasome, GSTO1-1, glutathione, NEK7, IL-1β, deglutathionylation, pyroptosis
