炎症体
泛素连接酶
吡喃结构域
细胞生物学
泛素
化学
炎症
机制(生物学)
自噬
受体
效应器
分泌物
免疫学
生物
生物化学
基因
细胞凋亡
认识论
哲学
作者
Zhuo Cheng,Menghao Huang,Wei Li,Lingling Hou,Li Jin,Qunbo Fan,Linqiang Zhang,Chengbin Li,Li Zeng,Chunzhang Yang,Bin Liang,Fubing Li,Ceshi Chen
标识
DOI:10.1038/s41419-024-06473-4
摘要
Abstract The NLRP3 inflammasome plays an important role in protecting the host from infection and aseptic inflammation, and its regulatory mechanism is not completely understood. Dysregulation of NLRP3 can cause diverse inflammatory diseases. HECTD3 is a E3 ubiquitin ligase of the HECT family that has been reported to participate in autoimmune and infectious diseases. However, the relationship between HECTD3 and the NLRP3 inflammasome has not been well studied. Herein, we show that HECTD3 blocks the interaction between NEK7 and NLRP3 to inhibit NLRP3 inflammasome assembly and activation. In BMDMs, Hectd3 deficiency promotes the assembly and activation of NLRP3 inflammasome and the secretion of IL-1β, while the overexpression of HECTD3 inhibits these processes. Unexpectedly, HECTD3 functions in an E3 activity independent manner. Mechanically, the DOC domain of HECTD3 interacts with NACHT/LRR domain of NLRP3, which blocks NLRP3-NEK7 interaction and NLRP3 oligomerization. Furthermore, HECTD3 inhibits monosodium urate crystals (MSU)-induced gouty arthritis, a NLRP3-related disease. Thus, we reveal a novel regulatory mechanism of NLRP3 by HECTD3 and suggest HECTD3 could be a potential therapeutic target for NLRP3-dependent pathologies.
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