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 XieJonathan B. Baell, Philip G. Board, Luke A.J. O'Neill^*

^*Corresponding author for this work

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

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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 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

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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{2b2064db7d4d407a8953d3c085ab9b0a,

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 = "GSTO1-1, IL-1β, NEK7, NLRP3 inflammasome, deglutathionylation, glutathione, 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 = "2211-1247",

publisher = "Elsevier B.V.",

number = "1",

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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 - GSTO1-1

KW - IL-1β

KW - NEK7

KW - NLRP3 inflammasome

KW - deglutathionylation

KW - glutathione

KW - pyroptosis

UR - http://www.scopus.com/inward/record.url?scp=85072286883&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2019.08.072

DO - 10.1016/j.celrep.2019.08.072

M3 - Article

SN - 2211-1247

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

Abstract

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