Cytosolic FKBPL and ER-resident CKAP4 co-regulates ER-phagy and protein secretion

Cathena Meiling Li, Jaemin Kang, Jongyeon Baek, Youbin Kim, Heemin Park and Yong-Keun Jung ()
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Cathena Meiling Li: Seoul National University
Jaemin Kang: Seoul National University
Jongyeon Baek: Seoul National University
Youbin Kim: Seoul National University
Heemin Park: Seoul National University
Yong-Keun Jung: Seoul National University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Endoplasmic reticulum quality control is crucial for maintaining cellular homeostasis and adapting to stress conditions. Although several ER-phagy receptors have been identified, the collaboration between cytosolic and ER-resident factors in ER fragmentation and ER-phagy regulation remains unclear. Here, we perform a phenotype-based gain-of-function screen and identify a cytosolic protein, FKBPL, functioning as an ER-phagy regulator. Overexpression of FKBPL triggers ER fragmentation and ER-phagy. FKBPL has multiple protein binding domains, can self-associate and might act as a scaffold connecting CKAP4 and LC3/GABARAPs. CKAP4 serves as a bridge between FKBPL and ER-phagy cargo. ER-phagy-inducing conditions increase FKBPL-CKAP4 interaction followed by FKBPL oligomerization at the ER, leading to ER-phagy. In addition, FKBPL-CKAP4 deficiency leads to Golgi disassembly and lysosome impairment, and an increase in ER-derived secretory vesicles and enhances cytosolic protein secretion via microvesicle shedding. Taken together, FKBPL with the aid of CKAP4 induces ER fragmentation and ER-phagy, and FKBPL-CKAP4 deficiency facilitates protein secretion.

Date: 2024
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DOI: 10.1038/s41467-024-52188-7

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