Glutathione Transferase Omega-1 Regulates NLRP3 Inflammasome Activation through NEK7 Deglutathionylation
Glutathione Transferase Omega-1 Regulates NLRP3 Inflammasome Activation through NEK7 Deglutathionylation
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DOI：
10.1016/j.celrep.2019.08.072
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发表时间：
2019-10-01
期刊：
影响因子：
8.8
通讯作者：
O'Neill, Luke A. J.
中科院分区：
文献类型：
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作者：
Hughes, Mark M.;Hooftman, Alexander;O'Neill, Luke A. J.
NLRP3炎性小体是一种胞质复合体，可感知被吞噬物质和各种损伤相关的分子模式，触发促炎细胞因子白细胞介素-1 β (IL)-1 β和IL-18的产生，并促进热亡。在这里，我们描述谷胱甘肽转移酶- 1-1 (GSTO1-1)，一种组成型谷胱甘肽酰化酶，作为NLRP3炎症小体的调节剂。通过GSTO1-1小分子抑制剂C1-27、内源性GSTO1-1敲低和GSTO1-1（-/-）小鼠，我们报道GSTO1-1参与NLRP3炎性体激活。机制上，GSTO1-1去谷胱甘肽使NIMA相关激酶7 （NEK7）中的半胱氨酸253磷酸化，促进NLRP3活化。因此，我们确定GSTO1-1是NLRP3炎症小体调节剂，具有作为限制NLRP3介导炎症的药物靶点的潜力。
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)-1 beta 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.