| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
Cell Reports, Vol 29, Iss 1, Pp 151-161.e5 (2019) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2019.08.072 |
| Popis: |
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 |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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