1. Academic Validation
  2. ACBD3 modulates KDEL receptor interaction with PKA for its trafficking via tubulovesicular carrier

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

  • BMC Biol. 2021 Sep 7;19(1):194. doi: 10.1186/s12915-021-01137-7.
Xihua Yue  # 1 Yi Qian  # 1 Lianhui Zhu 1 Bopil Gim 2 Mengjing Bao 1 Jie Jia 1 3 Shuaiyang Jing 1 3 Yijing Wang 1 3 Chuanting Tan 1 3 Francesca Bottanelli 4 Pascal Ziltener 5 Sunkyu Choi 6 Piliang Hao 1 Intaek Lee 7 8
Affiliations

Affiliations

  • 1 School of Life Science and Technology, ShanghaiTech University, Pudong, Shanghai, China.
  • 2 School of Physical Science and Technology, ShanghaiTech University, Pudong, Shanghai, China.
  • 3 University of Chinese Academy of Sciences, Beijing, China.
  • 4 Institut für Biochemie, Freie Universität Berlin, Thielallee 63, 14195, Berlin, Germany.
  • 5 Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
  • 6 Proteomics Core, Weill Cornell Medicine-Qatar, Doha, Qatar.
  • 7 School of Life Science and Technology, ShanghaiTech University, Pudong, Shanghai, China. Leeintaek@shanghaitech.edu.cn.
  • 8 Shanghai Institute for Advanced Immunochemical Studies, Shanghai, China. Leeintaek@shanghaitech.edu.cn.
  • # Contributed equally.
Abstract

Background: KDEL 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.

Results: We 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.

Conclusions: These 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.

Keywords

ACBD3; Arf1-GTP; ArfGAPs; Golgi; KDEL receptor; Protein Kinase A.

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