A network of chaperones prevents and detects failures in membrane protein lipid bilayer integration
A network of chaperones prevents and detects failures in membrane protein lipid bilayer integration
复制标题
分子伴侣网络可预防和检测膜蛋白脂质双层整合的失败
DOI：
10.1038/s41467-019-08632-0
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发表时间：
2019-02-08
影响因子：
16.6
通讯作者：
Feige, Matthias J.
中科院分区：
文献类型：
--
作者：
Coelho, Joao P. L.;Stahl, Matthias;Feige, Matthias J.
膜蛋白生物合成的一个基本步骤是它们以每个跨膜片段的确定方向整合到脂质双层中。尽管如此，目前仍不清楚细胞如何检测和处理这一过程中的故障。在这里，我们表明，单点突变的膜蛋白连接蛋白32（Cx 32），导致腓骨肌萎缩症，可导致膜整合失败。这导致Cx 32运输缺陷和快速降解。我们的数据表明，多个分子伴侣检测和补救这种异常行为：ER-膜复合物（EMC）有助于低疏水性跨膜片段的膜整合。如果它们不能整合，则这些被ER-内腔伴侣BiP识别。最终，E3连接酶gp 78泛素化Cx 32蛋白，靶向它们进行降解。因此，细胞使用分子伴侣的协调系统来完成膜蛋白生物合成的复杂任务，这可能会受到单点突变的影响，从而导致人类疾病。
A fundamental step in membrane protein biogenesis is their integration into the lipid bilayer with a defined orientation of each transmembrane segment. Despite this, it remains unclear how cells detect and handle failures in this process. Here we show that single point mutations in the membrane protein connexin 32 (Cx32), which cause Charcot-Marie-Tooth disease, can cause failures in membrane integration. This leads to Cx32 transport defects and rapid degradation. Our data show that multiple chaperones detect and remedy this aberrant behavior: the ER–membrane complex (EMC) aids in membrane integration of low-hydrophobicity transmembrane segments. If they fail to integrate, these are recognized by the ER–lumenal chaperone BiP. Ultimately, the E3 ligase gp78 ubiquitinates Cx32 proteins, targeting them for degradation. Thus, cells use a coordinated system of chaperones for the complex task of membrane protein biogenesis, which can be compromised by single point mutations, causing human disease.