LDO proteins and Vac8 form a vacuole-lipid droplet contact site required for lipophagy in response to starvation

Abstract

Lipid droplets (LDs) are fat storage organelles critical for energy and lipid metabolism. Upon nutrient exhaustion, cells consume LDs via gradual lipolysis or via lipophagy, the en bloc uptake of LDs into the vacuole. Here, we show that LDs dock to the vacuolar membrane via a contact site that is required for lipophagy in yeast. The LD-localized LDO proteins carry an intrinsically disordered region that associates with vacuolar Vac8 to form vCLIP, the vacuolar-LD contact site. Nutrient limitation drives vCLIP formation, and its inactivation blocks lipophagy. Vac8 is sufficient to recruit LDs to cellular membranes. We establish a functional link between lipophagy and microautophagy of the nucleus, both requiring Vac8 to form respective contact sites upon metabolic stress. In sum, we unravel the molecular architecture of vCLIP, a contact site required for lipophagy, and find that Vac8 provides a platform for multiple and competing contact sites associated with autophagy.

A unifying mechanism for seipin‐mediated lipid droplet formation

“…Ldo45 favors LD growth and TAG accumulation, while Ldo16 appears to function primarily during LD consumption through lipophagy [51,52]. In fact, recently, a new role of mediating LD tethering to the vacuole was described for Ldo16 due to its interaction with the vacuolar protein Vac8 [67,68]. In the absence of Ldo16, Ldo45 can also interact with Vac8 [67,68].…”

“…In fact, recently, a new role of mediating LD tethering to the vacuole was described for Ldo16 due to its interaction with the vacuolar protein Vac8 [67,68]. In the absence of Ldo16, Ldo45 can also interact with Vac8 [67,68]. As Ldo45 encompasses Ldo16, it is plausible that the ability of Ldo16 to target LDs in the vacuole is retained in Ldo45.…”

Remodelling of mitochondrial function by import of specific lipids at multiple membrane‐contact sites

“…Vps39 is recruited to the vacuole by the small GTPase Ypt7 [152][153][154]. A recent set of preprints further discovered a third interface between these organelles called vCLIP [155,156]. Although the function of these interfaces is not yet completely clear they all seem to be under the control of nutrient signaling and are probably involved in metabolic homeostasis, which is especially important during nutrient starvation.…”