Department of Biology, Stanford University, Stanford, CA 94305.
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2023 Apr 18;120(16):e2220340120. doi: 10.1073/pnas.2220340120. Epub 2023 Apr 10.
Ribosomes that stall while translating cytosolic proteins are incapacitated by incomplete nascent chains, termed "arrest peptides" (APs) that are destroyed by the ubiquitin proteasome system (UPS) via a process known as the ribosome-associated quality control (RQC) pathway. By contrast, APs on ribosomes that stall while translocating secretory proteins into the endoplasmic reticulum (ER-APs) are shielded from cytosol by the ER membrane and the tightly sealed ribosome-translocon junction (RTJ). How this junction is breached to enable access of cytosolic UPS machinery and 26S proteasomes to translocon- and ribosome-obstructing ER-APs is not known. Here, we show that UPS and RQC-dependent degradation of ER-APs strictly requires conjugation of the ubiquitin-like (Ubl) protein UFM1 to 60S ribosomal subunits at the RTJ. Therefore, UFMylation of translocon-bound 60S subunits modulates the RTJ to promote access of proteasomes and RQC machinery to ER-APs.
在翻译细胞质蛋白时停顿的核糖体被称为“阻滞肽”（APs）的不完全新生链所失活，这些肽通过泛素蛋白酶体系统（UPS）通过称为核糖体相关质量控制（RQC）途径被破坏。相比之下，在将分泌蛋白转运到内质网（ER-APs）时停顿的核糖体上的 AP 被内质网膜和紧密密封的核糖体转运物连接（RTJ）屏蔽在细胞质之外。尚不清楚如何破坏该连接，以使细胞质 UPS 机制和 26S 蛋白酶体能够进入易位蛋白和核糖体阻塞的 ER-APs。在这里，我们表明 UPS 和 RQC 依赖性 ER-AP 降解严格需要在 RTJ 处将泛素样（Ubl）蛋白 UFM1 缀合到 60S 核糖体亚基上。因此，易位蛋白结合的 60S 亚基的 UFMylation 调节 RTJ 以促进蛋白酶体和 RQC 机制进入 ER-APs。
