VPS13B maintains lysosomal homeostasis through regulation of TFEB

Abstract Cohen syndrome (CS) is a rare autosomal recessive neurodevelopmental disorder characterized by intellectual disability, microcephaly, retinal dystrophy, and neutropenia. We previously demonstrated that VPS13B mediates phosphatidylinositol 4-phosphate (PI4P) transport to promote mitochondrial fission. Here, we identify VPS13B as a regulator of lysosomal homeostasis. VPS13B knockout (KO) HeLa cells exhibited aberrant lysosomal distribution and reduction in LAMP1-positive lysosomes. Bulk RNA sequencing revealed coordinated downregulation of lysosome-related genes, including genes required for acidification and lysosome biogenesis, which was confirmed by quantitative RT-PCR. Consistent with these transcriptional changes, VPS13B KO significantly reduced the abundance of LysoTracker-positive acidic compartments. Induced neurons derived from CS patient iPSCs recapitulated the loss of acidic lysosomal compartments, supporting disease relevance. Mechanistically, VPS13B KO altered TFEB mRNA levels and modestly increased the basal nuclear-to-cytoplasmic (N/C) ratio of endogenous TFEB, but blunted its further increase upon Torin1 treatment. Together, these findings identify VPS13B as a regulator of lysosomal homeostasis and provide insight into how VPS13B deficiency may contribute to Cohen syndrome pathology.