RalA and PLD1 promote lipid droplet growth in response to nutrient withdrawal
Syed S. Hussain,
Tuyet-Minh Tran,
Timothy B. Ware,
Melissa A. Luse,
Christopher T. Prevost,
Ashley N. Ferguson,
Jennifer A. Kashatus,
Ku-Lung Hsu,
David F. Kashatus
Affiliations
Syed S. Hussain
Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
Tuyet-Minh Tran
Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
Timothy B. Ware
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA
Melissa A. Luse
Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
Christopher T. Prevost
Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
Ashley N. Ferguson
Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
Jennifer A. Kashatus
Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
Ku-Lung Hsu
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA; University of Virginia Cancer Center, University of Virginia Health System, Charlottesville, VA 22903, USA
David F. Kashatus
Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA; University of Virginia Cancer Center, University of Virginia Health System, Charlottesville, VA 22903, USA; Corresponding author
Summary: Lipid droplets (LDs) are dynamic organelles that undergo dynamic changes in response to changing cellular conditions. During nutrient depletion, LD numbers increase to protect cells against toxic fatty acids generated through autophagy and provide fuel for beta-oxidation. However, the precise mechanisms through which these changes are regulated have remained unclear. Here, we show that the small GTPase RalA acts downstream of autophagy to directly facilitate LD growth during nutrient depletion. Mechanistically, RalA performs this function through phospholipase D1 (PLD1), an enzyme that converts phosphatidylcholine (PC) to phosphatidic acid (PA) and that is recruited to lysosomes during nutrient stress in a RalA-dependent fashion. RalA inhibition prevents recruitment of the LD-associated protein perilipin 3, which is required for LD growth. Our data support a model in which RalA recruits PLD1 to lysosomes during nutrient deprivation to promote the localized production of PA and the recruitment of perilipin 3 to expanding LDs.
