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

57 Pages Posted: 29 Jan 2019 Sneak Peek Status: Published

See all articles by Mark M. Hughes

Mark M. Hughes

Trinity College (Dublin) - School of Biochemistry and Immunology

Alexander Hooftman

Trinity College (Dublin) - School of Biochemistry and Immunology

Stefano Angiari

Trinity College (Dublin) - School of Biochemistry and Immunology

Padmaja Tummala

Australian National University (ANU) - John Curtin School of Medical Research

Zbigniew Zaslona

Trinity College (Dublin) - School of Biochemistry and Immunology

Marah Runtsch

Trinity College (Dublin) - School of Biochemistry and Immunology

Eva Palsson Mc-Dermott

Trinity College (Dublin) - School of Biochemistry and Immunology

Ciana Diskin

Trinity College (Dublin) - School of Biochemistry and Immunology

Melissa Rooke

Australian National University (ANU) - John Curtin School of Medical Research

Shuhei Takahashi

Tokyo Medical and Dental University - Department of Human Pathology

Srinivasan Sundararaj

Australian National University (ANU) - John Curtin School of Medical Research

Marco G. Casarotto

Australian National University (ANU) - John Curtin School of Medical Research

Jane E. Dahlstrom

The Canberra Hospital - ACT Pathology

Sinead C. Corr

Trinity College (Dublin) - Department of Microbiology

Caroline E. Sutton

Trinity College (Dublin) - School of Biochemistry and Immunology

Anne F. McGettrick

Trinity College (Dublin) - School of Biochemistry and Immunology

Kingston H.G. Mills

Trinity College (Dublin) - School of Biochemistry and Immunology

Nouri Neamati

University of Southern California - Department of Pharmacology and Pharmaceutical Sciences

Yiyue Xie

Monash University - Monash Institute of Pharmaceutical Sciences

Jonathan B. Baell

Monash University - Monash Institute of Pharmaceutical Sciences

Roger J. S. Preston

Royal College of Surgeons in Ireland - Molecular and Cellular Therapeutics

Philip G. Board

Australian National University (ANU) - John Curtin School of Medical Research

Luke A. J. O’Neill

Trinity College (Dublin) - School of Biochemistry and Immunology

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Abstract

The NLRP3 inflammasome is a cytosolic complex sensing phagocytosed material and various damage associated molecular patterns, triggering production of the proinflammatory cytokines IL-1β and IL-18, promoting pyroptosis. Here, we characterise Glutathione transferase omega 1-1 (GSTO1-1), a constitutive deglutathionylating enzyme, as a novel NLRP3 inflammasome regulator. 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. GSTO1-1 is therefore identified as an NLRP3 inflammasome regulator, which has potential as a drug target to limit NLRP3-mediated inflammation.

Suggested Citation

Hughes, Mark M. and Hooftman, Alexander and Angiari, Stefano and Tummala, Padmaja and Zaslona, Zbigniew and Runtsch, Marah and Mc-Dermott, Eva Palsson and Diskin, Ciana and Rooke, Melissa and Takahashi, Shuhei and Sundararaj, Srinivasan and Casarotto, Marco G. and Dahlstrom, Jane E. and Corr, Sinead C. and Sutton, Caroline E. and McGettrick, Anne F. and Mills, Kingston H.G. and Neamati, Nouri and Xie, Yiyue and Baell, Jonathan B. and Preston, Roger J. S. and Board, Philip G. and O’Neill, Luke A. J., Glutathione Transferase Omega-1 Regulates NLRP3 Inflammasome Activation Through NEK7 Deglutathionylation (January 26, 2019). Available at SSRN: https://ssrn.com/abstract=3323379 or http://dx.doi.org/10.2139/ssrn.3323379
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Mark M. Hughes

Trinity College (Dublin) - School of Biochemistry and Immunology

2-3 College Green
Dublin, Leinster
Ireland

Alexander Hooftman

Trinity College (Dublin) - School of Biochemistry and Immunology

2-3 College Green
Dublin, Leinster
Ireland

Stefano Angiari

Trinity College (Dublin) - School of Biochemistry and Immunology

2-3 College Green
Dublin, Leinster
Ireland

Padmaja Tummala

Australian National University (ANU) - John Curtin School of Medical Research

131 Garran Road
Canberra, Australian Capital Territory 2601
Australia

Zbigniew Zaslona

Trinity College (Dublin) - School of Biochemistry and Immunology

2-3 College Green
Dublin, Leinster
Ireland

Marah Runtsch

Trinity College (Dublin) - School of Biochemistry and Immunology

2-3 College Green
Dublin, Leinster
Ireland

Eva Palsson Mc-Dermott

Trinity College (Dublin) - School of Biochemistry and Immunology

2-3 College Green
Dublin, Leinster
Ireland

Ciana Diskin

Trinity College (Dublin) - School of Biochemistry and Immunology

2-3 College Green
Dublin, Leinster
Ireland

Melissa Rooke

Australian National University (ANU) - John Curtin School of Medical Research

131 Garran Road
Canberra, Australian Capital Territory 2601
Australia

Shuhei Takahashi

Tokyo Medical and Dental University - Department of Human Pathology

1-5-45 Yushima
Bunkyo-ku
Tokyo, 1138519
Japan

Srinivasan Sundararaj

Australian National University (ANU) - John Curtin School of Medical Research

131 Garran Road
Canberra, Australian Capital Territory 2601
Australia

Marco G. Casarotto

Australian National University (ANU) - John Curtin School of Medical Research

131 Garran Road
Canberra, Australian Capital Territory 2601
Australia

Jane E. Dahlstrom

The Canberra Hospital - ACT Pathology

Canberra, 2606
Australia

Sinead C. Corr

Trinity College (Dublin) - Department of Microbiology

2-3 College Green
Dublin, Leinster
Ireland

Caroline E. Sutton

Trinity College (Dublin) - School of Biochemistry and Immunology

2-3 College Green
Dublin, Leinster
Ireland

Anne F. McGettrick

Trinity College (Dublin) - School of Biochemistry and Immunology

2-3 College Green
Dublin, Leinster
Ireland

Kingston H.G. Mills

Trinity College (Dublin) - School of Biochemistry and Immunology

2-3 College Green
Dublin, Leinster
Ireland

Nouri Neamati

University of Southern California - Department of Pharmacology and Pharmaceutical Sciences

2250 Alcazar Street
Los Angeles, CA 90089
United States

Yiyue Xie

Monash University - Monash Institute of Pharmaceutical Sciences

23 Innovation Walk
Wellington Road
Clayton, Victoria 3800
Australia

Jonathan B. Baell

Monash University - Monash Institute of Pharmaceutical Sciences

23 Innovation Walk
Wellington Road
Clayton, Victoria 3800
Australia

Roger J. S. Preston

Royal College of Surgeons in Ireland - Molecular and Cellular Therapeutics

123 St Stephens Green
Dublin 2
Ireland

Philip G. Board

Australian National University (ANU) - John Curtin School of Medical Research

131 Garran Road
Canberra, Australian Capital Territory 2601
Australia

Luke A. J. O’Neill (Contact Author)

Trinity College (Dublin) - School of Biochemistry and Immunology ( email )

2-3 College Green
Dublin, Leinster
Ireland

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