MYO18B promotes lysosomal exocytosis by facilitating focal adhesion maturation

ABSTRACT: Many cancer cells exhibit increased amounts of paucimannose glycans, which are truncated N-glycan structures rarely found in mammals. Paucimannosidic proteins are proposedly generated within lysosomes and exposed on the cell surface through a yet uncertain mechanism. In this study, we assured that paucimannosidic proteins in cancer cells are produced by lysosomal glycoside hydrolases and secreted via regulated lysosomal exocytosis, a process in which lysosomes are directly fused with the plasma membrane. Interestingly, lysosomal exocytosis preferentially occurred in the vicinity of focal adhesions, protein complexes connecting the actin cytoskeleton to the extracellular matrix. Through genome-wide knockout screening, we identified that MYO18B, an actin crosslinker, is required for focal adhesion maturation, facilitating lysosomal exocytosis and release of lysosomal proteins to the extracellular milieu. Our data suggest that the mechanosensitive cation channel PIEZO1 locally activated at focal adhesions imports Ca2+ necessary for lysosome-plasma membrane fusion. Collectively, our study unveiled an intimate relationship between lysosomal exocytosis and focal adhesion, shedding light on the unexpected interplay between lysosomal activities and cellular mechanosensing in cancer.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Rebeca Kawahara  

LAB HEAD: Morihisa Fujita

PROVIDER: PXD051592 | Pride | 2025-01-14

REPOSITORIES: pride