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

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Listed:
  • 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
    Seoul National University)

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.

Suggested Citation

  • Cathena Meiling Li & Jaemin Kang & Jongyeon Baek & Youbin Kim & Heemin Park & Yong-Keun Jung, 2024. "Cytosolic FKBPL and ER-resident CKAP4 co-regulates ER-phagy and protein secretion," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52188-7
    DOI: 10.1038/s41467-024-52188-7
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