CLSTN3B enhances lipid droplet function via endoplasmic reticulum contacts

Inter-organellar contact sites facilitate material exchanges between membrane-bound intracellular compartments and sustain the structural and functional integrity of organelles1-3. The endoplasmic reticulum (ER)-lipid droplet (LD) contact sites contribute to LD biogenesis and lipid transfer between the ER and LDs4-11. LDs in adipocytes are significantly larger than in non-adipocytes and crucial for energy storage and mobilization in response to body needs12-14. How adipocytes employ cell type-specific mechanisms to suppress unregulated lipolysis while remaining responsive to catecholamine-induced lipolysis is incompletely understood. Here we show that the mammalian adipocyte-specific protein Calsyntenin 3β (CLSTN3B) works at the ER/LD interface to enhance LD functionality. We found that CLSTN3B harbors an N-terminal LD-targeting and a C-terminal ER transmembrane domain linked by an arginine-rich segment, promoting a tight association between the ER and LDs. CLSTN3B-deficient LDs have reduced surface phospholipids density and decreased binding of LD-targeting proteins, hence more prone to leakage of free fatty acids (FFA) and less responsive to catecholamine-induced lipolysis than wild-type (WT) LDs. Furthermore, clstn3b knockout (clstn3b-/-) mice are more susceptible to high fat diet-induced metabolic complications than adiposity-matched WT mice, consistent with impaired LD functionality and compromised lipid-storing capacity of adipocytes. Our results demonstrate how CLSTN3B-mediated inter-organellar communication shapes LD functionality and translates into physiological significance at the animal level15