Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Cell Rep. 2020 Nov 17;33(7):108405. doi: 10.1016/j.celrep.2020.108405.
The NLRP3 inflammasome, a critical component of the innate immune system, induces caspase-1 activation and interleukin (IL)-1β maturation in response to microbial infection and cellular damage. However, aberrant activation of the NLRP3 inflammasome contributes to the pathogenesis of several inflammatory disorders, including cryopyrin-associated periodic syndromes, Alzheimer's disease, type 2 diabetes, and atherosclerosis. Here, we identify the receptor for activated protein C kinase 1 (RACK1) as a component of the NLRP3 complexes in macrophages. RACK1 interacts with NLRP3 and NEK7 but not ASC. Suppression of RACK1 expression abrogates caspase-1 activation and IL-1β release in response to NLRP3- but not NLRC4- or AIM2-activating stimuli. This RACK1 function is independent of its ribosomal binding activity. Mechanistically, RACK1 promotes the active conformation of NLRP3 induced by activating stimuli and subsequent inflammasome assembly. These results demonstrate that RACK1 is a critical mediator for NLRP3 inflammasome activation.
NLRP3 炎性小体是先天免疫系统的关键组成部分，可响应微生物感染和细胞损伤诱导半胱天冬酶-1 的激活和白细胞介素（IL）-1β 的成熟。然而，NLRP3 炎性小体的异常激活导致几种炎症性疾病的发病机制，包括 Cryopyrin 相关周期性综合征、阿尔茨海默病、2 型糖尿病和动脉粥样硬化。在这里，我们确定激活蛋白 C 激酶 1（RACK1）受体为巨噬细胞中 NLRP3 复合物的一个组成部分。RACK1 与 NLRP3 和 NEK7 相互作用，但不与 ASC 相互作用。抑制 RACK1 表达可消除对 NLRP3 而不是 NLRC4 或 AIM2 激活刺激的半胱天冬酶-1 激活和 IL-1β 释放。这种 RACK1 功能不依赖于其核糖体结合活性。从机制上讲，RACK1 促进了激活刺激诱导的 NLRP3 的活性构象，并随后进行炎性小体组装。这些结果表明 RACK1 是 NLRP3 炎性小体激活的关键介质。
