Work

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

Year: 2026

Type: article

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.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2026.113612