Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival
Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival
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Sel1L 对于哺乳动物内质网相关降解、内质网稳态和生存是不可或缺的。
DOI：
10.1073/pnas.1318114111
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发表时间：
2014-02-04
影响因子：
11.1
通讯作者：
Qi, Ling
中科院分区：
文献类型：
--
作者：
Sun, Shengyi;Shi, Guojun;Qi, Ling
LIN-12抑制/增强因子(Sel1L)是参与内质网相关降解(ERAD)的E3连接酶羟甲基戊二酰基还原酶降解蛋白1(Hrd1)的接头蛋白。然而，Sel1L在哺乳动物ERAD中的生理重要性仍有待确定。在这里，使用可诱导的Sel1L基因敲除小鼠和细胞模型，我们表明Sel1L对于Hrd1的稳定性、内质网稳态和生存是不可或缺的。急性丢失Sel1L会导致成年小鼠在3周内过早死亡，并伴有严重的胰腺萎缩。与目前的看法相反，我们的数据表明哺乳动物的Sel1L在体外和体内都是Hrd1稳定和ERAD功能所必需的。Sel1L缺乏扰乱内质网稳态，激活内质网应激，减弱翻译，促进细胞死亡。偶然的是，使用生化方法结合质谱分析，我们发现Sel1L缺乏会导致核糖体小亚基和大亚基的聚集。因此，Sel1L是哺乳动物Hrd1 ERAD复合体和ER动态平衡不可或缺的组成部分，对蛋白质翻译、胰腺功能以及细胞和生物生存至关重要。
Suppressor/Enhancer of Lin-12-like (Sel1L) is an adaptor protein for the E3 ligase hydroxymethylglutaryl reductase degradation protein 1 (Hrd1) involved in endoplasmic reticulum-associated degradation (ERAD). Sel1L's physiological importance in mammalian ERAD, however, remains to be established. Here, using the inducible Sel1L knockout mouse and cell models, we show that Sel1L is indispensable for Hrd1 stability, ER homeostasis, and survival. Acute loss of Sel1L leads to premature death in adult mice within 3 wk with profound pancreatic atrophy. Contrary to current belief, our data show that mammalian Sel1L is required for Hrd1 stability and ERAD function both in vitro and in vivo. Sel1L deficiency disturbs ER homeostasis, activates ER stress, attenuates translation, and promotes cell death. Serendipitously, using a biochemical approach coupled with mass spectrometry, we found that Sel1L deficiency causes the aggregation of both small and large ribosomal subunits. Thus, Sel1L is an indispensable component of the mammalian Hrd1 ERAD complex and ER homeostasis, which is essential for protein translation, pancreatic function, and cellular and organismal survival.