A metabolically controlled contact site between lipid droplets and vacuoles

Abstract

The lipid droplet (LD) organization proteins Ldo16 and Ldo45 affect multiple aspects of LD biology in yeast. They are linked to the LD biogenesis machinery seipin, and their loss causes defects in LD positioning, protein targeting, and breakdown. However, their molecular roles remained enigmatic. Here we report that Ldo16/45 form a tether-complex with Vac8 for creation of vacuole lipid droplet (vCLIP) contact sites, which can form in the absence of seipin. The phosphatidylinositol transfer protein Pdr16 is a further vCLIP-resident recruited by Ldo45. While only an LD-subpopulation is engaged in vCLIPs at glucose-replete conditions, nutrient stress results in vCLIP expansion, and vCLIP defects impair lipophagy upon prolonged starvation. In summary, Ldo16/45 are multifunctional proteins that orchestrate formation of a metabolically-regulated contact site. Our studies suggest an unexpected link between LD biogenesis and breakdown, and open the door to a deeper understanding of how lipid homeostasis is maintained during metabolic challenges.

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.…”

Molecular determinants of lipid droplet subpopulations and their fates

“…Another question is how Pdr16 influences NVJ-associated LDs. It is clearly recruited by Ldo45 to LDs [13], but its specific role in micro-lipophagy remains unclear. Of note, Pdr16 is a Sec14 homolog with predicted phosphoinositol lipid transport activity that influences LD homeostasis [14], but more recent reports indicate it may also transport ergosterol precursors in addition to phospholipids [15].…”

“…composition that influence the process [8]. Pdr16 was also denoted as a LD subset-specific protein that enriches on NVJ-associated LDs, suggesting these LDs may have unique lipid compositions [1].…”

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.…”