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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	151-161.e5
Journal	Cell Reports
Volume	29
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2019.08.072
Publication status	Published - 1 Oct 2019
Externally published	Yes

Keywords

deglutathionylation
glutathione
GSTO1-1
IL-1β
NEK7
NLRP3 inflammasome
pyroptosis

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10.1016/j.celrep.2019.08.072

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Hughes, M. M., Hooftman, A., Angiari, S., Tummala, P., Zaslona, Z., Runtsch, M. C., McGettrick, A. F., Sutton, C. E., Diskin, C., Rooke, M., Takahashi, S., Sundararaj, S., Casarotto, M. G., Dahlstrom, J. E., Palsson-McDermott, E. M., Corr, S. C., Mills, K. H. G., Preston, R. J. S., Neamati, N., ... O'Neill, L. A. J. (2019). Glutathione Transferase Omega-1 Regulates NLRP3 Inflammasome Activation through NEK7 Deglutathionylation. Cell Reports, 29(1), 151-161.e5. https://doi.org/10.1016/j.celrep.2019.08.072

@article{7e828608c1fc43748e43a9230cbceac3,

title = "Glutathione Transferase Omega-1 Regulates NLRP3 Inflammasome Activation through NEK7 Deglutathionylation",

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 = "deglutathionylation, glutathione, GSTO1-1, IL-1β, NEK7, NLRP3 inflammasome, pyroptosis",

author = "Hughes, \{Mark M.\} and Alexander Hooftman and Stefano Angiari and Padmaja Tummala and Zbigniew Zaslona and Runtsch, \{Marah C.\} and McGettrick, \{Anne F.\} and Sutton, \{Caroline E.\} and Ciana Diskin and Melissa Rooke and Shuhei Takahashi and Srinivasan Sundararaj and Casarotto, \{Marco G.\} and Dahlstrom, \{Jane E.\} and Palsson-McDermott, \{Eva M.\} and Corr, \{Sinead C.\} and Mills, \{Kingston H.G.\} and Preston, \{Roger J.S.\} and Nouri Neamati and Yiyue Xie and Baell, \{Jonathan B.\} and Board, \{Philip G.\} and O'Neill, \{Luke A.J.\}",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = oct,

day = "1",

doi = "10.1016/j.celrep.2019.08.072",

language = "English",

volume = "29",

pages = "151--161.e5",

journal = "Cell Reports",

issn = "2639-1856",

publisher = "Elsevier B.V.",

number = "1",

}

Hughes, MM, Hooftman, A, Angiari, S, Tummala, P, Zaslona, Z, Runtsch, MC, McGettrick, AF, Sutton, CE, Diskin, C, Rooke, M, Takahashi, S, Sundararaj, S, Casarotto, MG, Dahlstrom, JE, Palsson-McDermott, EM, Corr, SC, Mills, KHG, Preston, RJS, Neamati, N, Xie, Y, Baell, JB, Board, PG & O'Neill, LAJ 2019, 'Glutathione Transferase Omega-1 Regulates NLRP3 Inflammasome Activation through NEK7 Deglutathionylation', Cell Reports, vol. 29, no. 1, pp. 151-161.e5. https://doi.org/10.1016/j.celrep.2019.08.072

TY - JOUR

T1 - Glutathione Transferase Omega-1 Regulates NLRP3 Inflammasome Activation through NEK7 Deglutathionylation

AU - Hughes, Mark M.

AU - Hooftman, Alexander

AU - Angiari, Stefano

AU - Tummala, Padmaja

AU - Zaslona, Zbigniew

AU - Runtsch, Marah C.

AU - McGettrick, Anne F.

AU - Sutton, Caroline E.

AU - Diskin, Ciana

AU - Rooke, Melissa

AU - Takahashi, Shuhei

AU - Sundararaj, Srinivasan

AU - Casarotto, Marco G.

AU - Dahlstrom, Jane E.

AU - Palsson-McDermott, Eva M.

AU - Corr, Sinead C.

AU - Mills, Kingston H.G.

AU - Preston, Roger J.S.

AU - Neamati, Nouri

AU - Xie, Yiyue

AU - Baell, Jonathan B.

AU - Board, Philip G.

AU - O'Neill, Luke A.J.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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.

KW - deglutathionylation

KW - glutathione

KW - GSTO1-1

KW - IL-1β

KW - NEK7

KW - NLRP3 inflammasome

KW - pyroptosis

UR - https://www.scopus.com/pages/publications/85072286883

U2 - 10.1016/j.celrep.2019.08.072

DO - 10.1016/j.celrep.2019.08.072

M3 - Article

C2 - 31577945

AN - SCOPUS:85072286883

SN - 2639-1856

VL - 29

SP - 151-161.e5

JO - Cell Reports

JF - Cell Reports

IS - 1

ER -

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

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Keywords

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