Numerous proteins that have hydrophobic transmembrane domains (TMDs) traverse the cytosol and posttranslationally insert into cellular membranes. It is unclear how these hydrophobic membrane proteins evade recognition by the cytosolic protein quality control (PQC), which typically recognizes exposed hydrophobicity in misfolded proteins and marks them for proteasomal degradation by adding ubiquitin chains. Here, we find that tail-anchored (TA) proteins, a vital class of membrane proteins, are recognized by cytosolic PQC and are ubiquitinated as soon as they are synthesized in cells. Surprisingly, the ubiquitinated TA proteins are not routed for proteasomal degradation but instead are handed over to the targeting factor, TRC40, and delivered to the ER for insertion. The ER-associated deubiquitinases, USP20 and USP33, remove ubiquitin chains from TA proteins after their insertion into the ER. Thus, our data suggest that deubiquitinases rescue posttranslationally targeted membrane proteins that are inappropriately ubiquitinated by PQC in the cytosol.

中文翻译：

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去泛素酶USP20 / 33促进尾锚膜蛋白的生物发生。

具有疏水跨膜结构域（TMD）的许多蛋白质穿过细胞质并翻译后插入细胞膜。尚不清楚这些疏水膜蛋白如何逃避胞质蛋白质量控制（PQC）的识别，质控通常可识别错误折叠的蛋白中暴露的疏水性，并通过添加泛素链将其标记为蛋白酶体降解。在这里，我们发现，尾锚（TA）蛋白是一种重要的膜蛋白，可被胞质PQC识别，并在细胞中合成后立即泛素化。出人意料的是，泛素化的TA蛋白没有被路由进行蛋白酶体降解，而是被转移到靶向因子TRC40，并被传递到ER进行插入。ER相关的去泛素酶USP20和USP33，将TA蛋白插入ER后，从TA蛋白中去除泛素链。因此，我们的数据表明去泛素酶可以挽救被胞质溶胶中PQC泛素化的翻译后靶向膜蛋白。