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Peer-reviewedCC BY-NC-ND 4.0The Journal of Biological Chemistry

CAPZ regulates endosomal–exosomal trafficking of plasma membrane PD-L1 independently of canonical autophagy

  • Peng Xu1
  • Zuodong Ye2
  • Yanni Zhu1,3
  • Chuen-Fuk Chan1
  • Yanhua Li1,3
  • Huiru Huang1
  • Chengyi Zhu1
  • Xiaoyin Zhang1
  • Yijing Wang1
  • Yilin Wang1
  • Naixin Lin4
  • Wei Sun5
3 more authors
  • Meiyu Peng3
  • Yingying Lu6
  • Jianbo Yue1,3,7
7 affiliations
  1. 1Division of Natural and Applied Sciences, Synear Molecular Biology Lab, Jiangsu Provincial University Key (Construction) Laboratory for Smart Diagnosis and Treatment of Lung Cancer, Duke Kunshan University, Kunshan, China
  2. 2Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Key Laboratory for Prevention and Control of Avian Influenza and Other Major Poultry Diseases, Ministry of Agriculture and Rural Affairs, Guangzhou, China
  3. 3School of Basic Medical Sciences, Shandong Second Medical University, Weifang, China
  4. 4City University of Hong Kong Shenzhen Research Institute, Shenzhen, China
  5. 5Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
  6. 6Department of Research Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
  7. 7College of Life Sciences, Wuhan University, Wuhan, China
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Abstract

Programmed death-ligand 1 (PD-L1) undergoes continuous endocytosis and post-endocytic sorting that determine its recycling to the plasma membrane, lysosomal degradation, and exosomal secretion. Although PD-L1 internalization depends on RAB5-mediated endocytosis, whether canonical autophagy contributes to the subsequent sorting of internalized PD-L1 remains unclear. Here, we show that canonical autophagy is dispensable for the post-endocytic fate of cell-surface PD-L1. Genetic disruption of core autophagy components, including LC3B, ATG4B, ATG5, and ATG7, did not impair delivery of internalized PD-L1 to early endosomes, multivesicular bodies (MVBs), late endosomes, or extracellular vesicles. Pharmacologic inhibition of autophagosome–lysosome fusion increased PD-L1 accumulation in RAB5- and CD63-positive compartments, but this effect persisted in cells lacking LC3B, ATG5, or ATG7, further indicating that canonical autophagy is not required for PD-L1 endosomal sorting or exosomal secretion. Instead, we identify CAPZ, a CAPZα–CAPZβ heterodimer best known for actin filament capping, as a regulator of PD-L1 post-endocytic sorting. Loss of CAPZ reduced PD-L1 delivery to CD63-positive MVBs and incorporation into exosomes while increasing its accumulation in RAB11-positive recycling endosomes, resulting in elevated cell-surface PD-L1. Functionally, CAPZ-deficient tumor cells were less sensitive to peripheral blood mononuclear cell-mediated killing, consistent with increased surface PD-L1 and enhanced immune-evasive capacity. Together, these findings indicate that CAPZ-dependent endosomal maturation controls the balance between PD-L1 recycling and MVB/exosomal sorting independently of canonical autophagy, thereby influencing PD-L1 surface abundance and tumor immune evasion.

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Cite

BibTeXRIS
BibTeX
@article{xu2026capz,
  title = {{CAPZ regulates endosomal–exosomal trafficking of plasma membrane PD-L1 independently of canonical autophagy}},
  author = {Peng Xu and Zuodong Ye and Yanni Zhu and Chuen-Fuk Chan and Yanhua Li and Huiru Huang and Chengyi Zhu and Xiaoyin Zhang and Yijing Wang and Yilin Wang and Naixin Lin and Wei Sun and Meiyu Peng and Yingying Lu and Jianbo Yue},
  journal = {The Journal of Biological Chemistry},
  year = {2026},
  month = sep,
  doi = {10.1016/j.jbc.2026.113612},
  url = {https://doi.org/10.1016/j.jbc.2026.113612},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - CAPZ regulates endosomal–exosomal trafficking of plasma membrane PD-L1 independently of canonical autophagy
AU  - Peng Xu
AU  - Zuodong Ye
AU  - Yanni Zhu
AU  - Chuen-Fuk Chan
AU  - Yanhua Li
AU  - Huiru Huang
AU  - Chengyi Zhu
AU  - Xiaoyin Zhang
AU  - Yijing Wang
AU  - Yilin Wang
AU  - Naixin Lin
AU  - Wei Sun
AU  - Meiyu Peng
AU  - Yingying Lu
AU  - Jianbo Yue
PY  - 2026
DA  - 2026/09/29
JO  - The Journal of Biological Chemistry
DO  - 10.1016/j.jbc.2026.113612
UR  - https://doi.org/10.1016/j.jbc.2026.113612
AB  - Programmed death-ligand 1 (PD-L1) undergoes continuous endocytosis and post-endocytic sorting that determine its recycling to the plasma membrane, lysosomal degradation, and exosomal secretion. Although PD-L1 internalization depends on RAB5-mediated endocytosis, whether canonical autophagy contributes to the subsequent sorting of internalized PD-L1 remains unclear. Here, we show that canonical autophagy is dispensable for the post-endocytic fate of cell-surface PD-L1. Genetic disruption of core autophagy components, including LC3B, ATG4B, ATG5, and ATG7, did not impair delivery of internalized PD-L1 to early endosomes, multivesicular bodies (MVBs), late endosomes, or extracellular vesicles. Pharmacologic inhibition of autophagosome–lysosome fusion increased PD-L1 accumulation in RAB5- and CD63-positive compartments, but this effect persisted in cells lacking LC3B, ATG5, or ATG7, further indicating that canonical autophagy is not required for PD-L1 endosomal sorting or exosomal secretion. Instead, we identify CAPZ, a CAPZα–CAPZβ heterodimer best known for actin filament capping, as a regulator of PD-L1 post-endocytic sorting. Loss of CAPZ reduced PD-L1 delivery to CD63-positive MVBs and incorporation into exosomes while increasing its accumulation in RAB11-positive recycling endosomes, resulting in elevated cell-surface PD-L1. Functionally, CAPZ-deficient tumor cells were less sensitive to peripheral blood mononuclear cell-mediated killing, consistent with increased surface PD-L1 and enhanced immune-evasive capacity. Together, these findings indicate that CAPZ-dependent endosomal maturation controls the balance between PD-L1 recycling and MVB/exosomal sorting independently of canonical autophagy, thereby influencing PD-L1 surface abundance and tumor immune evasion.
SN  - 0021-9258
SN  - 1083-351X
ER  -