Lipid droplets modulate proteostasis, SQST-1/SQSTM1 dynamics, and lifespan in C. elegans
Anita V. Kumar,
Joslyn Mills,
Wesley M. Parker,
Joshua A. Leitão,
Diego I. Rodriguez,
Sandrine E. Daigle,
Celeste Ng,
Rishi Patel,
Joseph L. Aguilera,
Joseph R. Johnson,
Shi Quan Wong,
Louis R. Lapierre
Affiliations
Anita V. Kumar
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Providence, RI 02912, USA
Joslyn Mills
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Providence, RI 02912, USA; Biology Department, Wheaton College, 26 E. Main Street, Norton, MA 02766, USA
Wesley M. Parker
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Providence, RI 02912, USA
Joshua A. Leitão
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Providence, RI 02912, USA
Diego I. Rodriguez
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Providence, RI 02912, USA
Sandrine E. Daigle
New Brunswick Center for Precision Medicine, 27 rue Providence, Moncton, NB E1C 8X3, Canada; Département de chimie et biochimie, Université de Moncton, 18 Antonine Maillet, Moncton, NB E1A 3E9, Canada
Celeste Ng
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Providence, RI 02912, USA
Rishi Patel
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Providence, RI 02912, USA
Joseph L. Aguilera
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Providence, RI 02912, USA
Joseph R. Johnson
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Providence, RI 02912, USA
Shi Quan Wong
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Providence, RI 02912, USA
Louis R. Lapierre
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Providence, RI 02912, USA; New Brunswick Center for Precision Medicine, 27 rue Providence, Moncton, NB E1C 8X3, Canada; Département de chimie et biochimie, Université de Moncton, 18 Antonine Maillet, Moncton, NB E1A 3E9, Canada; Corresponding author
Summary: In several long-lived Caenorhabditis elegans strains, such as insulin/IGF-1 receptor daf-2 mutants, enhanced proteostatic mechanisms are accompanied by elevated intestinal lipid stores, but their role in longevity is unclear. Here, while determining the regulatory network of the selective autophagy receptor SQST-1/SQSTM1, we uncovered an important role for lipid droplets in proteostasis and longevity. Using genome-wide RNAi screening, we identified several SQST-1 modulators, including lipid droplets-associated and aggregation-prone proteins. Expansion of intestinal lipid droplets by silencing the conserved cytosolic triacylglycerol lipase gene atgl-1/ATGL enhanced autophagy, and extended lifespan. Notably, a substantial amount of ubiquitinated proteins were found on lipid droplets. Reducing lipid droplet levels exacerbated the proteostatic collapse when autophagy or proteasome function was compromised, and significantly reduced the lifespan of long-lived daf-2 animals. Altogether, our study uncovered a key role for lipid droplets in C. elegans as a proteostatic mediator that modulates ubiquitinated protein accumulation, facilitates autophagy, and promotes longevity.
