DIP2 is a unique regulator of diacylglycerol lipid homeostasis in eukaryotes
- Centre for Cellular and Molecular Biology, India
- Indian Institute of Science Education and Research Pune, India
Abstract
Chain-length specific subsets of diacylglycerol (DAG) lipids are proposed to regulate differential physiological responses ranging from signal transduction to modulation of the membrane properties. However, the mechanism or molecular players regulating the subsets of DAG species remains unknown. Here, we uncover the role of a conserved eukaryotic protein family, DISCO-interacting protein 2 (DIP2) as a homeostatic regulator of a chemically distinct subset of DAGs using yeast, fly and mouse models. Genetic and chemical screens along with lipidomics analysis in yeast reveal that DIP2 prevents the toxic accumulation of specific DAGs in the logarithmic growth phase, which otherwise leads to endoplasmic reticulum stress. We also show that the fatty acyl-AMP ligase-like domains of DIP2 are essential for the redirection of the flux of DAG subspecies to storage lipid, triacylglycerols. DIP2 is associated with vacuoles through mitochondria-vacuole contact sites and such modulation of selective DAG abundance by DIP2 is found to be crucial for optimal vacuole membrane fusion and consequently osmoadaptation in yeast. Thus, the study illuminates an unprecedented DAG metabolism route and provides new insights on how cell fine-tunes DAG subspecies for cellular homeostasis and environmental adaptation.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for all figures in the manuscript.
Article and author information
Author details
Priyadarshan Kinatukara
Rajan Sankaranarayanan
Funding
Council for Scientific and Industrial Research , India
- Sudipta Mondal
Department of Biotechnology, Ministry of Science and Technology, India
- Priyadarshan Kinatukara
University Grants Commission
- Sakshi Shambhavi
DBT/Wellcome Trust India Alliance Fellowship (IA/I/15/2/502058)
- Siddhesh S Kamat
Department of Science and Technology, Ministry of Science and Technology, India (SR/FST/LSII-043/2016)
- Siddhesh S Kamat
J.C. Bose Fellowship
- Rajan Sankaranarayanan
NCP under health care theme project
- Rajan Sankaranarayanan
Centre of Excellence Project
- Rajan Sankaranarayanan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was carried out in strict accordance with the recommendations in the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), India. The protocols were approved by the Institutional Animal Ethics Committee (IAEC) of CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India (20/ GO/RBi/99/CPCSEA). All terminal experiments were performed by cervical dislocation after anesthetizing with isoflurane. All efforts were made to minimize suffering during all experiments.
Reviewing Editor
- Felix Campelo, Institute of Photonic Sciences, Spain
Publication history
- Preprint posted: February 7, 2022 (view preprint)
- Received: February 7, 2022
- Accepted: June 28, 2022
- Accepted Manuscript published: June 29, 2022 (version 1)
- Version of Record published: August 1, 2022 (version 2)
Copyright
© 2022, Mondal et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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DIP2 is a unique regulator of diacylglycerol lipid homeostasis in eukaryotes
eLife 11:e77665.
https://doi.org/10.7554/eLife.77665
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