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Substrate ubiquitination retains misfolded membrane proteins in the endoplasmic reticulum for degradation
Cell Reports ( IF 8.8 ) Pub Date : 2021-09-21 , DOI: 10.1016/j.celrep.2021.109717
Zhihao Sun 1 , Christopher J Guerriero 1 , Jeffrey L Brodsky 1
Affiliation  

To maintain secretory pathway fidelity, misfolded proteins are commonly retained in the endoplasmic reticulum (ER) and selected for ER-associated degradation (ERAD). Soluble misfolded proteins use ER chaperones for retention, but the machinery that restricts aberrant membrane proteins to the ER is unclear. In fact, some misfolded membrane proteins escape the ER and traffic to the lysosome/vacuole. To this end, we describe a model substrate, SZ, that contains an ER export signal but is also targeted for ERAD. We observe decreased ER retention when chaperone-dependent SZ ubiquitination is compromised. In addition, appending a linear tetra-ubiquitin motif onto SZ overrides ER export. By screening known ubiquitin-binding proteins, we then positively correlate SZ retention with Ubx2 binding. Deletion of Ubx2 also inhibits the retention of another misfolded membrane protein. Our results indicate that polyubiquitination is sufficient to retain misfolded membrane proteins in the ER prior to ERAD.



中文翻译:

底物泛素化在内质网中保留错误折叠的膜蛋白以进行降解

为了保持分泌途径的保真度,错误折叠的蛋白质通常保留在内质网 (ER) 中并选择用于 ER 相关降解 (ERAD)。可溶性错误折叠蛋白使用 ER 伴侣进行保留,但将异常膜蛋白限制到 ER 的机制尚不清楚。事实上,一些错误折叠的膜蛋白会逃离 ER 并运输到溶酶体/液泡。为此,我们描述了一个模型底物 SZ *,它包含一个 ER 输出信号,但也是 ERAD 的目标。当依赖伴侣的 SZ *泛素化受到损害时,我们观察到 ER 保留减少。此外,将线性四泛素基序附加到 SZ 覆盖 ER 导出。通过筛选已知的泛素结合蛋白,我们将 SZ *保留与 Ubx2 结合正相关。Ubx2 的删除也抑制了另一种错误折叠的膜蛋白的保留。我们的结果表明,多泛素化足以在 ERAD 之前将错误折叠的膜蛋白保留在 ER 中。

更新日期:2021-09-21
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