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

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

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 languageEnglish
Pages (from-to)151-161.e5
Number of pages11
JournalCell Reports
Volume29
Issue number1
DOIs
Publication statusPublished - 1 Oct 2019

Keywords

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

Cite this

Hughes, M. M., Hooftman, A., Angiari, S., Tummala, P., Zaslona, Z., Runtsch, M. C., ... 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
Hughes, Mark M. ; Hooftman, Alexander ; Angiari, Stefano ; Tummala, Padmaja ; Zaslona, Zbigniew ; Runtsch, Marah C. ; McGettrick, Anne F. ; Sutton, Caroline E. ; Diskin, Ciana ; Rooke, Melissa ; Takahashi, Shuhei ; Sundararaj, Srinivasan ; Casarotto, Marco G. ; Dahlstrom, Jane E. ; Palsson-McDermott, Eva M. ; Corr, Sinead C. ; Mills, Kingston H.G. ; Preston, Roger J.S. ; Neamati, Nouri ; Xie, Yiyue ; Baell, Jonathan B. ; Board, Philip G. ; O'Neill, Luke A.J. / Glutathione Transferase Omega-1 Regulates NLRP3 Inflammasome Activation through NEK7 Deglutathionylation. In: Cell Reports. 2019 ; Vol. 29, No. 1. pp. 151-161.e5.
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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.",
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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

Glutathione Transferase Omega-1 Regulates NLRP3 Inflammasome Activation through NEK7 Deglutathionylation. / Hughes, Mark M.; Hooftman, Alexander; Angiari, Stefano; Tummala, Padmaja; Zaslona, Zbigniew; Runtsch, Marah C.; McGettrick, Anne F.; Sutton, Caroline E.; Diskin, Ciana; Rooke, Melissa; Takahashi, Shuhei; Sundararaj, Srinivasan; Casarotto, Marco G.; Dahlstrom, Jane E.; Palsson-McDermott, Eva M.; Corr, Sinead C.; Mills, Kingston H.G.; Preston, Roger J.S.; Neamati, Nouri; Xie, Yiyue; Baell, Jonathan B.; Board, Philip G.; O'Neill, Luke A.J.

In: Cell Reports, Vol. 29, No. 1, 01.10.2019, p. 151-161.e5.

Research output: Contribution to journalArticleResearchpeer-review

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.

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KW - glutathione

KW - GSTO1-1

KW - IL-1β

KW - NEK7

KW - NLRP3 inflammasome

KW - pyroptosis

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Hughes MM, Hooftman A, Angiari S, Tummala P, Zaslona Z, Runtsch MC et al. Glutathione Transferase Omega-1 Regulates NLRP3 Inflammasome Activation through NEK7 Deglutathionylation. Cell Reports. 2019 Oct 1;29(1):151-161.e5. https://doi.org/10.1016/j.celrep.2019.08.072