Ubiquitination-mediated regulation of biosynthesis of the adhesion receptor SHPS-1 in response to endoplasmic reticulum stress
Ubiquitination-mediated regulation of biosynthesis of the adhesion receptor SHPS-1 in response to endoplasmic reticulum stress
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DOI：
10.1074/jbc.m311463200
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发表时间：
2004-03-19
影响因子：
4.8
通讯作者：
Kasuga, M
中科院分区：
文献类型：
--
作者：
Murai-Takebe, R;Noguchi, T;Kasuga, M
内质网（ER）应激过程中蛋白质的错误折叠导致细胞毒性聚集体的形成。ER相关的降解途径通过泛素-蛋白酶体系统消除错误折叠的蛋白质来抵消这种聚集。我们现在表明，SHP底物-1（SHPS-1），一种调节细胞骨架重组和细胞间通讯的跨膜糖蛋白，是Skp 1-Cullin 1-NFB 42-Rbx 1（SCFNFB 42）E3泛素连接酶的生理底物，E3泛素连接酶是一种ER相关降解的介体。SCFNFB 42介导未成熟SHPS-1的多聚泛素化及其被蛋白酶体降解。NFB 42的异位表达既抑制了攻击样结构的形成，又抑制了由SHPS-1过度产生诱导的翻译调节因子eIF 2 α的磷酸化，同时增加了细胞表面成熟SHPS-1的量。缺乏F盒结构域的NFB 42突变体没有这样的效果。我们的研究结果表明，SCFNFB 42调节SHPS-1的生物合成响应ER应力。
Misfolding of proteins during endoplasmic reticulum (ER) stress results in the formation of cytotoxic aggregates. The ER-associated degradation pathway counteracts such aggregation through the elimination of misfolded proteins by the ubiquitin-proteasome system. We now show that SHP substrate-1 (SHPS-1), a transmembrane glycoprotein that regulates cytoskeletal reorganization and cell-cell communication, is a physiological substrate for the Skp1-Cullin1-NFB42-Rbx1 (SCFNFB42) E3 ubiquitin ligase, a proposed mediator of ER-associated degradation. SCFNFB42 mediated the polyubiquitination of immature SHPS-1 and its degradation by the proteasome. Ectopic expression of NFB42 both suppressed the formation of aggresome-like structures and the phosphorylation of the translational regulator eIF2alpha induced by overproduction of SHPS-1 as well as increased the amount of mature SHPS-1 at the cell surface. An NFB42 mutant lacking the F box domain had no such effects. Our results suggest that SCFNFB42 regulates SHPS-1 biosynthesis in response to ER stress.