ARL8B mediates lipid droplet contact and delivery to lysosomes for lipid remobilization

Lipid droplets (LDs) play a crucial role in maintaining cellular lipid balance by storing and delivering lipids as needed. However, the intricate lipolytic pathways involved in LD turnover remain poorly described, hindering our comprehension of lipid catabolism and related disorders. Here, we show a function of the small GTPase ARL8B in mediating LD turnover in lysosomes. ARL8B-GDP localizes to LDs, while ARL8-GTP predominantly favors lysosomes. GDP binding induces a conformation with an exposed N-terminal amphipathic helix, enabling ARL8B to bind to LDs. By associating with LDs and lysosomes, and with its property to form a heterotypic complex, ARL8B mediates LD-lysosome contacts and efficient lipid transfer between these organelles. In human macrophages, this ARL8B-dependent LD turnover mechanism appears as the major lipolytic pathway. Our finding opens exciting possibilities for understanding the molecular mechanisms underlying LD degradation and its potential implications for inflammatory disorders. [Display omitted] •ARL8B promotes lysosomal lipolysis of LD-stored triacylglycerol•ARL8B-GDP associates with LD and ARL8B-GTP predominantly with lysosomes•ARL8B facilitates LD-lysosome contacts wherein the GDP- and GTP-bound states form a complex•ARL8B-mediated lysosomal lipolysis of LDs is a neutral lipid turnover pathway in macrophages Menon et al. show that ARL8B, a small GTPase, mediates direct lysosome-dependent LD turnover by interacting with both LDs and lysosomes.