ACBD3 modulates KDEL receptor interaction with PKA for its trafficking via tubulovesicular carrier

BMC Biology

Pascal Ziltener¹  Francesca Bottanelli²  Sunkyu Choi³  Piliang Hao⁴  Lianhui Zhu⁴  Mengjing Bao⁴  Xihua Yue⁴  Yi Qian⁴  Intaek Lee⁵  Yijing Wang⁶  Chuanting Tan⁶  Shuaiyang Jing⁶  Jie Jia⁶  Bopil Gim⁷ 

[1] Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA;Institut für Biochemie, Freie Universität Berlin, Thielallee 63, 14195, Berlin, Germany;Proteomics Core, Weill Cornell Medicine-Qatar, Doha, Qatar;School of Life Science and Technology, ShanghaiTech University, Pudong, Shanghai, China;School of Life Science and Technology, ShanghaiTech University, Pudong, Shanghai, China;Shanghai Institute for Advanced Immunochemical Studies, Shanghai, China;School of Life Science and Technology, ShanghaiTech University, Pudong, Shanghai, China;University of Chinese Academy of Sciences, Beijing, China;School of Physical Science and Technology, ShanghaiTech University, Pudong, Shanghai, China;

关键词: KDEL receptor;    Protein Kinase A;    ACBD3;    ArfGAPs;    Arf1-GTP;    Golgi;   

DOI  :  10.1186/s12915-021-01137-7

来源: Springer

【 摘 要 】

BackgroundKDEL receptor helps establish cellular equilibrium in the early secretory pathway by recycling leaked ER-chaperones to the ER during secretion of newly synthesized proteins. Studies have also shown that KDEL receptor may function as a signaling protein that orchestrates membrane flux through the secretory pathway. We have recently shown that KDEL receptor is also a cell surface receptor, which undergoes highly complex itinerary between trans-Golgi network and the plasma membranes via clathrin-mediated transport carriers. Ironically, however, it is still largely unknown how KDEL receptor is distributed to the Golgi at steady state, since its initial discovery in late 1980s.ResultsWe used a proximity-based in vivo tagging strategy to further dissect mechanisms of KDEL receptor trafficking. Our new results reveal that ACBD3 may be a key protein that regulates KDEL receptor trafficking via modulation of Arf1-dependent tubule formation. We demonstrate that ACBD3 directly interact with KDEL receptor and form a functionally distinct protein complex in ArfGAPs-independent manner. Depletion of ACBD3 results in re-localization of KDEL receptor to the ER by inducing accelerated retrograde trafficking of KDEL receptor. Importantly, this is caused by specifically altering KDEL receptor interaction with Protein Kinase A and Arf1/ArfGAP1, eventually leading to increased Arf1-GTP-dependent tubular carrier formation at the Golgi.ConclusionsThese results suggest that ACBD3 may function as a negative regulator of PKA activity on KDEL receptor, thereby restricting its retrograde trafficking in the absence of KDEL ligand binding. Since ACBD3 was originally identified as PAP7, a PBR/PKA-interacting protein at the Golgi/mitochondria, we propose that Golgi-localization of KDEL receptor is likely to be controlled by its interaction with ACBD3/PKA complex at steady state, providing a novel insight for establishment of cellular homeostasis in the early secretory pathway.

【 授权许可】

CC BY