PAQR9 Modulates BAG6-mediated protein quality control of mislocalized membrane proteins
PAQR9 Modulates BAG6-mediated protein quality control of mislocalized membrane proteins
复制标题
PAQR9 调节 BAG6 介导的错误定位膜蛋白的蛋白质质量控制
DOI：
10.1042/bcj20190620
复制
发表时间：
2020-01-01
影响因子：
4.1
通讯作者：
Chen, Yan
中科院分区：
文献类型：
--
作者：
You, Xue;Lin, Yijun;Chen, Yan
蛋白质质量控制对于维持细胞内稳态至关重要，其功能障碍与人类疾病密切相关。翻译后蛋白质的质量控制机制主要由BCL-2相关的产氨基因6（BAG6）组成，负责对错误定位的膜蛋白（MLP）进行分类。然而，尚不清楚BAG6介导的MLP降解是如何调节的。我们在这里报告，PAQR9，一个成员的Progressive和AdipoQ受体（PAQR）家庭，能够调节BAG6介导的分流的MLP。质谱分析鉴定BAG6是与PAQR9相互作用的主要蛋白质之一，并且这种相互作用通过共免疫沉淀和共定位测定来证实。代表性MLP的蛋白质降解速率通过PAQR9敲低而加速。因此，MLP的多聚泛素化通过PAQR9敲低而增强。PAQR9与BAG6的富含脯氨酸段内的DUF3538结构域结合。PAQR9以DUF3538结构域依赖性方式减少MLP与BAG6的结合。总之，我们的结果表明PAQR9通过影响BAG6与膜蛋白的相互作用在MLP的蛋白质质量控制的调节中起作用。
Protein quality control is crucial for maintaining cellular homeostasis and its dysfunction is closely linked to human diseases. The post-translational protein quality control machinery mainly composed of BCL-2-associated athanogene 6 (BAG6) is responsible for triage of mislocalized membrane proteins (MLPs). However, it is unknown how the BAG6-mediated degradation of MLPs is regulated. We report here that PAQR9, a member of the Progesterone and AdipoQ receptor (PAQR) family, is able to modulate BAG6-mediated triage of MLPs. Analysis with mass spectrometry identified that BAG6 is one of the major proteins interacting with PAQR9 and such interaction is confirmed by co-immunoprecipitation and co-localization assays. The protein degradation rate of representative MLPs is accelerated by PAQR9 knockdown. Consistently, the polyubiquitination of MLPs is enhanced by PAQR9 knockdown. PAQR9 binds to the DUF3538 domain within the proline-rich stretch of BAG6. PAQR9 reduces the binding of MLPs to BAG6 in a DUF3538 domain-dependent manner. Taken together, our results indicate that PAQR9 plays a role in the regulation of protein quality control of MLPs via affecting the interaction of BAG6 with membrane proteins.