Naismith, T. | Search bioRxiv

bioRxiv2024

DFCP1 is a Regulator of ATGL-mediated Lipid Droplet Lipolysis

Lipid droplets (LDs) are transient lipid storage organelles that can be readily tapped to resupply cells with energy or lipid building blocks, and therefore play a central role in cellular metabolism. Double FYVE Domain Containing Protein 1 (DFCP1/ZFYV1) has emerged as a key regulator of LD metabolism, where the nucleotide-dependent accumulation of DFCP1 on LDs influences their size, number, and dynamics. Here we show that DFCP1 regulates lipid metabolism by directly modulating the activity of Adipose Triglyceride Lipase (ATGL/PNPLA2), the rate-limiting lipase driving the catabolism of LDs. We show through pharmacological inhibition of key enzymes associated with LD metabolism that DFCP1 specifically regulates lipolysis and, to a lesser extent, lipophagy. Consistent with this observation, DFCP1 interacts with and recruits ATGL to LDs in starved cells, irrespective of known regulatory factors of ATGL. We further establish that this interaction prevents dynamic disassociation of ATGL from LDs and thereby impedes the rate of LD lipolysis. Collectively, our findings indicate that DFCP1 primes ATGL on LDs to promote rapid LD catabolism.

cell biology↗

bioRxiv2022

The GTPase Activity of the Double FYVE Domain Containing Protein 1 (DFCP1) Regulates Lipid Droplet Metabolism.

Lipid droplets (LDs) are transient lipid storage organelles that can be readily tapped to resupply cells with energy or lipid building blocks, and therefore play a central role in cellular metabolism. However, the molecular factors and underlying mechanisms that regulate the growth and degradation of LDs are poorly understood. It has emerged that LD metabolism is sensitive to the autophagy- and LD-associated protein Double FYVE Domain Containing Protein 1 (DFCP1), however, little is known about DFCP1s roles in autophagy and LD metabolism. Here, we show that DFCP1 contains a novel GTPase domain that regulates LD size by controlling the assembly of DFCP1 onto LDs in response to changes in nutrient availability. Specifically, we show that DFCP1 accumulation on LDs is independent of PI3P-binding, but requires a combination of the ER-binding domain and a unique GTPase domain. This novel GTPase domain possesses a low basal GTP turnover rate and has the ability to dimerize. Furthermore, mutations in the DFCP1 that either impact GTP hydrolysis or dimerization, result in changes in the accumulation of DFCP1 on LDs, as well as in changes in LD density and size. Importantly, the magnitude of these changes depends on the nutritional status of the cell. Collectively, our findings indicate that DFCP1 is a GTP-dependent metabolic sensor capable of modulating cellular storage of free fatty acids.

cell biology↗