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

Hooftman, Alexander; O'Neill, Luke

doi:https://doi-org.elib.tcd.ie/10.1016/j.celrep.2019.08.072

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

Files

1-s2.0-S2211124719311271-main.pdf (3.32 MB)

Date

2019

Authors

Hooftman, Alexander

O'Neill, Luke

Access

openAccess

Citation

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., Xie, Y., Baell, J.B., Board, P.G., O'Neill, L.A.J., Glutathione Transferase Omega-1 Regulates NLRP3 Inflammasome Activation through NEK7 Deglutathionylation, Cell Reports, 2019, Oct 1;29(1):151-161.e5.

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.