COP I and II dependent trafficking controls ER-associated degradation in mammalian cells

Navit Ogen-Shtern; Chieh Chang; Haddas Saad; Niv Mazkereth; Chaitanya Patel; Marina Shenkman; Gerardo Z Lederkremer

doi:10.1016/j.isci.2023.106232

COP I and II dependent trafficking controls ER-associated degradation in mammalian cells

iScience. 2023 Feb 19;26(3):106232. doi: 10.1016/j.isci.2023.106232. eCollection 2023 Mar 17.

Authors

Navit Ogen-Shtern^{1

2}, Chieh Chang^{1

2}, Haddas Saad^{1

2}, Niv Mazkereth^{1

2}, Chaitanya Patel^{1

2}, Marina Shenkman^{1

2}, Gerardo Z Lederkremer^{1

2}

Affiliations

¹ The Shmunis School of Biomedicine and Cancer Research, Cell Biology Division, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
² Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.

Abstract

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.

Keywords: Cell; Cell biology.