TY - JOUR
T1 - Mdm1 maintains endoplasmic reticulum homeostasis by spatially regulating lipid droplet biogenesis
AU - Hariri, Hanaa
AU - Speer, Natalie
AU - Bowerman, Jade
AU - Rogers, Sean
AU - Fu, Gang
AU - Reetz, Evan
AU - Datta, Sanchari
AU - Feathers, J. Ryan
AU - Ugrankar, Rupali
AU - Nicastro, Daniela
AU - Henne, W. Mike
N1 - Funding Information:
D. Nicastro is supported by Cancer Prevention and Research Institute of Texas grant RP140082. W.M. Henne is supported by grants from the Welch Foundation (I-1873), the Searle Foundation (SSP-2016-1482), the National Institutes of Health National Institute of General Medical Sciences (GM119768), American Federation for Aging Research (A15198), and the University of Texas Southwestern Endowed Scholars Program. The authors declare no competing financial interests.
Funding Information:
We thank Sandra Schmid and Joel Goodman for helpful discussions and critical reading of the manuscript. We thank Jonathan Friedman for helpful discussions. We thank Maya Schuldiner for sharing the yeast GFP collection. We thank Kate Luby-Phelps and the University of Texas Southwestern Electron Microscopy Core Facility for expert technical assistance. We thank Daniel Stoddard for training and management of the University of Texas Southwestern Medical Center Cryo-Electron Microscopy Facility that is supported in part by the Cancer Prevention and Research Institute of Texas Core Facility Support Award RP170644.
Publisher Copyright:
© 2019 Hariri et al.
PY - 2019
Y1 - 2019
N2 - Lipid droplets (LDs) serve as cytoplasmic reservoirs for energy-rich fatty acids (FAs) stored in the form of triacylglycerides (TAGs). During nutrient stress, yeast LDs cluster adjacent to the vacuole/lysosome, but how this LD accumulation is coordinated remains poorly understood. The ER protein Mdm1 is a molecular tether that plays a role in clustering LDs during nutrient depletion, but its mechanism of function remains unknown. Here, we show that Mdm1 associates with LDs through its hydrophobic N-terminal region, which is sufficient to demarcate sites for LD budding. Mdm1 binds FAs via its Phoxassociated domain and coenriches with fatty acyl-coenzyme A ligase Faa1 at LD bud sites. Consistent with this, loss of MDM1 perturbs free FA activation and Dga1-dependent synthesis of TAGs, elevating the cellular FA level, which perturbs ER morphology and sensitizes yeast to FA-induced lipotoxicity. We propose that Mdm1 coordinates FA activation adjacent to the vacuole to promote LD production in response to stress, thus maintaining ER homeostasis.
AB - Lipid droplets (LDs) serve as cytoplasmic reservoirs for energy-rich fatty acids (FAs) stored in the form of triacylglycerides (TAGs). During nutrient stress, yeast LDs cluster adjacent to the vacuole/lysosome, but how this LD accumulation is coordinated remains poorly understood. The ER protein Mdm1 is a molecular tether that plays a role in clustering LDs during nutrient depletion, but its mechanism of function remains unknown. Here, we show that Mdm1 associates with LDs through its hydrophobic N-terminal region, which is sufficient to demarcate sites for LD budding. Mdm1 binds FAs via its Phoxassociated domain and coenriches with fatty acyl-coenzyme A ligase Faa1 at LD bud sites. Consistent with this, loss of MDM1 perturbs free FA activation and Dga1-dependent synthesis of TAGs, elevating the cellular FA level, which perturbs ER morphology and sensitizes yeast to FA-induced lipotoxicity. We propose that Mdm1 coordinates FA activation adjacent to the vacuole to promote LD production in response to stress, thus maintaining ER homeostasis.
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U2 - 10.1083/jcb.201808119
DO - 10.1083/jcb.201808119
M3 - Article
C2 - 30808705
AN - SCOPUS:85064215578
SN - 0021-9525
VL - 218
SP - 1319
EP - 1334
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 4
ER -