炎性小体中ASC斑点形成机理及调控机制

Advances in formation and regulation of ASC-speck in inflammasome activation-A review

摘要:

在一系列微生物感染及内外源性刺激物的作用下，细胞质中多种蛋白复合物组装成炎性小体，其主要功能是活化半胱天冬酶-1，引起一系列促炎细胞因子的分泌和半胱天冬酶-1依赖性的细胞死亡。凋亡相关斑点样蛋白（ASC）是炎性小体中连接胞浆内受体和半胱天冬酶-1的接头蛋白，在炎性小体活化中ASC聚集成大分子的二聚体，被称为ASC斑点（ASC-speck）。ASC斑点的形成对半胱天冬酶-1的活化至关重要，调控ASC斑点的形成是炎性小体相关疾病的治疗和预防的新途径。本文从ASC斑点形成的分子机理，以及磷酸化、泛素化和去泛素化、离子通道等方面，对近年来ASC斑点的调控机制相关的研究进展进行综合评述，总结了ASC斑点的形成机理及主要调控机制，最后结合作者相关研究成果和观点对该领域的研究前景进行了展望。

Abstract:

Under the effects of a series of microbial infection and endogenous or exogenous stimuli, inflammasomes are assembled as multiple protein complexes in the cytoplasm, which mainly contain pattern recognition receptors (PRRs), apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1. The inflammasomes are the platform for caspase-1 activation and subsequent proinflammatory cytokines secretion, and caspase-1 dependent cell death as well. As a key adaptor protein, ASC concatenates PRRs and pro-caspase-1 in the cytoplasm. During inflammasome activation, ASC molecules assemble into large molecule dimers, which is called ASC-speck. The formation of ASC-speck is critical for caspase-1 activation, and ASC-speck becomes a target for the therapy and prevention of inflammatory diseases. In this review, advances in molecular mechanism of ASC-speck formation and the regulation systems for ASC-speck are summarized from the aspects of phosphorylation, ubiquitination and iron channels etc. Finally, the research prospects in this field are discussed.