Department of Biological Sciences, National University of Singapore, Singapore.
Eur J Immunol. 2010 Jun;40(6):1738-47. doi: 10.1002/eji.200940034.
SARM (sterile alpha- and armadillo-motif-containing protein), the fifth identified TIR (Toll-interleukin 1 receptor (IL-1R)) domain-containing adaptors in humans, downregulates NF-kappaB and IRF3 (interferon-regulatory factor 3)-mediated TLR3 and TLR4 signaling. SARM was characterized as a negative regulator of the TRIF (TIR-domain-containing adaptor protein inducing IFN-beta)-dependent pathway via its interaction with TRIF. However, the precise mechanism of action of SARM remains unclear. Here, we demonstrate that SARM inhibits MAPK activation in human embryonic kidney 293 cells, and U937 cells. Both the TRIF- and MyD88-mediated, as well as basal MAPK activity, were repressed, indicating that SARM-mediated inhibition may not be exclusively directed at TRIF or MyD88, but that SARM may also directly inhibit MAPK phosphorylation. The MAPK inhibition effect was verified by RNAi, which increased the basal level of AP-1. Furthermore, LPS challenge upregulated SARM at both the mRNA and protein levels. Finally, we provide evidence to show that truncated SARM changes its subcellular localization, suggesting the importance of the N-terminal and sterile alpha motif domains in the autoregulation of SARM activity.
SARM（ sterile alpha- and armadillo-motif-containing protein），是人类中第五个被鉴定的 TIR（Toll-interleukin 1 receptor (IL-1R)）结构域包含衔接蛋白，可下调 NF-kappaB 和 IRF3（干扰素调节因子 3）介导的 TLR3 和 TLR4 信号。SARM 通过与 TRIF 的相互作用被表征为 TRIF（TIR 结构域包含衔接蛋白诱导 IFN-β）依赖性途径的负调节剂。然而，SARM 的确切作用机制仍不清楚。在这里，我们证明 SARM 抑制人胚肾 293 细胞和 U937 细胞中的 MAPK 激活。TRIF 和 MyD88 介导的以及基础的 MAPK 活性均受到抑制，表明 SARM 介导的抑制作用可能不仅仅针对 TRIF 或 MyD88，而是 SARM 也可能直接抑制 MAPK 磷酸化。RNAi 验证了 MAPK 抑制作用，增加了 AP-1 的基础水平。此外，LPS 刺激在 mRNA 和蛋白质水平上均上调了 SARM。最后，我们提供了证据表明，截断的 SARM 改变了其亚细胞定位，这表明 N 端和无菌α基序结构域在 SARM 活性的自身调节中的重要性。
