The PAAD/PYRIN-family protein ASC is a dual regulator of a conserved step in nuclear factor κB activation pathways

被引:139
作者
Stehlik, C
Fiorentino, L
Dorfleutner, A
Bruey, JM
Ariza, EM
Sagara, J
Reed, JC
机构
[1] Burnham Inst, La Jolla, CA 92037 USA
[2] Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
[3] Shinshu Univ, Sch Med, Dept Mol Oncol, Res Ctr Aging & Adaptat, Nagano 3908621, Japan
关键词
inflammation; signal transduction; I kappa B kinase; monocytes; NF-kappa B;
D O I
10.1084/jem.20021552
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Apoptosis-associated speck-like protein containing a Caspase recruitment domain (ASC) belongs to a large family of proteins that contain a Pyrin, AIM, ASC, and death domain-like (PAAD) domain (also known as PYRIN, DAPIN, Pyk). Recent data have suggested that ASC functions as an adaptor protein linking various PAAD-family proteins to pathways involved in nuclear factor (NF)-kappaB and pro-Caspase-1 activation. We present evidence here that the role of ASC in modulating NF-kappaB activation pathways is much broader than previously suspected, as it can either inhibit or activate NF-kappaB, depending on cellular context. While coexpression of ASC with certain PAAD-family proteins such as Pyrin and Cryopyrin increases NF-kappaB activity, ASC has an inhibitory influence on NF-kappaB activation by various proinflammatory stimuli, including tumor necrosis factor (TNF)alpha, interleukin 1beta, and lipopolysaccharide (LPS). Elevations in ASC protein levels or of the PAAD domain of ASC suppressed activation of IkappaB kinases in cells exposed to pro-inflammatory stimuli. Conversely, reducing endogenous levels of ASC using siRNA enhanced TNF- and LPS-induced degradation of the IKK substrate, IkappaBalpha. Our findings suggest that ASC modulates diverse NF-kappaB induction pathways by acting upon the IKK complex, implying a broad role for this and similar proteins containing PAAD domains in regulation of inflammatory responses.
引用
收藏
页码:1605 / 1615
页数:11
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