Faculty, Staff and Student Publications
Publication Date
10-9-2023
Journal
EMBO Reports
Abstract
The maintenance of lysosome homeostasis is crucial for cell growth. Lysosome-dependent degradation and metabolism sustain tumor cell survival. Here, we demonstrate that CCDC50 serves as a lysophagy receptor, promoting tumor progression and invasion by controlling lysosomal integrity and renewal. CCDC50 monitors lysosomal damage, recognizes galectin-3 and K63-linked polyubiquitination on damaged lysosomes, and specifically targets them for autophagy-dependent degradation. CCDC50 deficiency causes the accumulation of ruptured lysosomes, impaired autophagic flux, and superfluous reactive oxygen species, consequently leading to cell death and tumor suppression. CCDC50 expression is associated with malignancy, progression to metastasis, and poor overall survival in human melanoma. Targeting CCDC50 suppresses tumor growth and lung metastasis, and enhances the effect of BRAFV600E inhibition. Thus, we demonstrate critical roles of CCDC50-mediated clearance of damaged lysosomes in supporting tumor growth, hereby identifying a potential therapeutic target of melanoma.
Keywords
Lysosomes, Humans, Homeostasis, Autophagy, Melanoma, Cell Line, Tumor, Animals, Cell Proliferation, Mice, Ubiquitination, Reactive Oxygen Species, Proto-Oncogene Proteins B-raf, CCDC50, cell death, lysophagy, lysosome damage, melanoma, Autophagy & Cell Death, Cancer, Organelles
DOI
10.15252/embr.202356948
PMID
37672005
PMCID
PMC10561174
PubMedCentral® Posted Date
September 2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Dermatology Commons, Medical Sciences Commons, Musculoskeletal Diseases Commons, Oncology Commons, Skin and Connective Tissue Diseases Commons