Tld1 is a regulator of triglyceride lipolysis that demarcates a lipid droplet subpopulation

Author:

Speer Natalie Ortiz1ORCID,Braun R. Jay2ORCID,Reynolds Emma Grace1ORCID,Brudnicka Alicja1ORCID,Swanson Jessica M.J.2ORCID,Henne W. Mike1ORCID

Affiliation:

1. The University of Texas Southwestern Medical Center 1 Department of Cell Biology, , Dallas, TX, USA

2. University of Utah 2 Department of Chemistry, , Salt Lake City, UT, USA

Abstract

Cells store lipids in the form of triglyceride (TG) and sterol ester (SE) in lipid droplets (LDs). Distinct pools of LDs exist, but a pervasive question is how proteins localize to and convey functions to LD subsets. Here, we show that the yeast protein YDR275W/Tld1 (for TG-associated LD protein 1) localizes to a subset of TG-containing LDs and reveal it negatively regulates lipolysis. Mechanistically, Tld1 LD targeting requires TG, and it is mediated by two distinct hydrophobic regions (HRs). Molecular dynamics simulations reveal that Tld1’s HRs interact with TG on LDs and adopt specific conformations on TG-rich LDs versus SE-rich LDs in yeast and human cells. Tld1-deficient yeast display no defect in LD biogenesis but exhibit elevated TG lipolysis dependent on lipase Tgl3. Remarkably, overexpression of Tld1, but not LD protein Pln1/Pet10, promotes TG accumulation without altering SE pools. Finally, we find that Tld1-deficient cells display altered LD mobilization during extended yeast starvation. We propose that Tld1 senses TG-rich LDs and regulates lipolysis on LD subpopulations.

Funder

Welch Foundation

National Institutes of Health

National Institute of General Medical Sciences

National Institute of Diabetes and Digestive and Kidney Diseases

Ara Parseghian Medical Research Fund

UT Southwestern Endowed Scholars Program

Pittsburgh Supercomputing Center

San Diego Supercomputing Center

National Science Foundation

University of Utah

Publisher

Rockefeller University Press

Subject

Cell Biology

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