Ogen-Shtern Navit, Chang Chieh, Saad Haddas, Mazkereth Niv, Patel Chaitanya, Shenkman Marina, Lederkremer Gerardo Z
The Shmunis School of Biomedicine and Cancer Research, Cell Biology Division, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.
iScience. 2023 Feb 19;26(3):106232. doi: 10.1016/j.isci.2023.106232. eCollection 2023 Mar 17.
Misfolded proteins and components of the endoplasmic reticulum (ER) quality control and ER associated degradation (ERAD) machineries concentrate in mammalian cells in the pericentriolar ER-derived quality control compartment (ERQC), suggesting it as a staging ground for ERAD. By tracking the chaperone calreticulin and an ERAD substrate, we have now determined that the trafficking to the ERQC is reversible and recycling back to the ER is slower than the movement in the ER periphery. The dynamics suggest vesicular trafficking rather than diffusion. Indeed, using dominant negative mutants of ARF1 and Sar1 or the drugs Brefeldin A and H89, we observed that COPI inhibition causes accumulation in the ERQC and increases ERAD, whereas COPII inhibition has the opposite effect. Our results suggest that targeting of misfolded proteins to ERAD involves COPII-dependent transport to the ERQC and that they can be retrieved to the peripheral ER in a COPI-dependent manner.
错误折叠的蛋白质以及内质网（ER）质量控制和ER相关降解（ERAD）机制的组分在哺乳动物细胞中聚集于源自中心粒周围内质网的质量控制区室（ERQC），这表明它是ERAD的一个准备阶段。通过追踪伴侣蛋白钙网蛋白和一个ERAD底物，我们现在确定了向ERQC的运输是可逆的，并且回收到内质网的过程比在内质网周边的移动要慢。这种动态变化表明是囊泡运输而非扩散。实际上，使用ARF1和Sar1的显性负性突变体或药物布雷菲德菌素A和H89，我们观察到抑制COPI会导致在ERQC中积累并增加ERAD，而抑制COPII则有相反的效果。我们的结果表明，将错误折叠的蛋白质靶向ERAD涉及COPII依赖性运输至ERQC，并且它们能够以COPII依赖性方式被回收至周边内质网。
