School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
Cell Rep. 2019 Oct 1;29(1):151-161.e5. doi: 10.1016/j.celrep.2019.08.072.
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 炎性小体是一种胞浆复合物，可感应吞噬的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-1β（IL-1β）和 IL-18 的产生，并促进细胞焦亡。在这里，我们将谷胱甘肽转移酶 omega 1-1（GSTO1-1）鉴定为 NLRP3 炎性小体的调节因子。我们使用 GSTO1-1 的小分子抑制剂 C1-27、内源性 GSTO1-1 敲低和 GSTO1-1 小鼠进行研究，报告 GSTO1-1 参与 NLRP3 炎性小体的激活。从机制上讲，GSTO1-1 使丝氨酸/苏氨酸激酶 NIMA 相关激酶 7（NEK7）中的半胱氨酸 253 去谷胱甘肽化，从而促进 NLRP3 的激活。因此，我们将 GSTO1-1 鉴定为 NLRP3 炎性小体的调节剂，它可能成为限制 NLRP3 介导的炎症的药物靶点。
