Protein quality control is a process in which a protein’s folding status is constantly monitored. Mislocalized proteins (MLP), are processed by the various quality control pathways, as they are often misfolded due to inappropriate cellular surroundings. Polypeptides that fail to translocate into the ER due to an inefficient signal peptide, mutations or ER stress are recognized by the pre-emptive ER associated quality control (pEQC) pathway and degraded by the 26 S proteasome. In this report we reveal the role of RNF149, a membrane bound E3 ligase in the ubiquitination of known pEQC substrates. We demonstrate its selective binding only to non-translocated proteins and its association with known pEQC components. Impairment in RNF149 function increases translocation flux into the ER and manifests in a myeloproliferative neoplasm (MPN) phenotype, a pathological condition associated with pEQC impairment. Finally, the dynamic localization of RNF149 may provide a molecular switch to regulate pEQC during ER stress.

蛋白质质量控​​制是一个不断监测蛋白质折叠状态的过程。错误定位的蛋白质 (MLP) 由各种质量控制途径处理，因为它们经常因不适当的细胞环境而错误折叠。由于低效信号肽、突变或 ER 应激而未能转移到 ER 中的多肽被先发制人的 ER 相关质量控制 (pEQC) 通路识别，并被 26 S 蛋白酶体降解。在本报告中，我们揭示了 RNF149 的作用，RNF149 是一种膜结合 E3 连接酶，在已知 pEQC 底物的泛素化中发挥作用。我们展示了它仅与非易位蛋白的选择性结合及其与已知 pEQC 成分的关联。RNF149 功能受损会增加进入 ER 的易位通量，并表现为骨髓增生性肿瘤 (MPN) 表型，与 pEQC 损伤相关的病理状况。最后，RNF149 的动态定位可能提供一个分子开关来调节 ER 应激期间的 pEQC。