Shang Limin, Tomasi Thomas B
Laboratory of Molecular Medicine, Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
J Biol Chem. 2006 Jan 27;281(4):1876-84. doi: 10.1074/jbc.M509901200. Epub 2005 Nov 9.
Interferon signaling pathways are critical to both innate and adaptive immunity. We have demonstrated here that the inhibition of heat shock protein 90 (Hsp90) functions by small interfering RNAs or chemical inhibitors blocking interferon-induced gene expression. Hsp90 was required for signal transducers and activators of transcription 1 phosphorylation, and in its absence, Janus kinase (JAK) 1/2 were degraded by the proteosome. JAK1 interacts with Hsp90 and the CDC37 co-chaperone, and both interactions are destabilized by Hsp90 inhibitors. The biological consequences were suggested by experiments showing that T cell activation by interferon-gamma-primed macrophages and the antiviral response of interferons required Hsp90. We conclude that JAK1/2 are client proteins of Hsp90 and that Hsp90 and CDC37 play a critical role in types I and II interferon pathways.
干扰素信号通路对先天性免疫和适应性免疫都至关重要。我们在此证明，小干扰RNA或化学抑制剂对热休克蛋白90（Hsp90）功能的抑制会阻断干扰素诱导的基因表达。信号转导子和转录激活子1的磷酸化需要Hsp90，在没有Hsp90的情况下，Janus激酶（JAK）1/2会被蛋白酶体降解。JAK1与Hsp90和CDC37共伴侣相互作用，而这两种相互作用都会被Hsp90抑制剂破坏。实验表明，γ干扰素预处理的巨噬细胞对T细胞的激活以及干扰素的抗病毒反应都需要Hsp90，这提示了其生物学后果。我们得出结论，JAK1/2是Hsp90的客户蛋白，并且Hsp90和CDC37在I型和II型干扰素通路中起关键作用。
