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.
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 version of the paper has not been formally peer reviewed.
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