DIP2 is a unique regulator of diacylglycerol lipid homeostasis in eukaryotes

  1. Sudipta Mondal
  2. Priyadarshan Kinatukara
  3. Shubham Singh
  4. Sakshi Shambhavi
  5. Gajanan S Patil
  6. Noopur Dubey
  7. Salam Herojeet Singh
  8. Biswajit Pal
  9. P Chandra Shekar
  10. Siddhesh S Kamat
  11. Rajan Sankaranarayanan  Is a corresponding author
  1. Centre for Cellular and Molecular Biology, India
  2. 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

  1. Sudipta Mondal

    Structural Biology, Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3923-7449
  2. Priyadarshan Kinatukara

    Structural Biology, Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2210-2369
  3. Shubham Singh

    Department of Biology, Indian Institute of Science Education and Research Pune, Pune, India
    Competing interests
    No competing interests declared.
  4. Sakshi Shambhavi

    Structural Biology, Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8852-1542
  5. Gajanan S Patil

    Structural Biology, Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
  6. Noopur Dubey

    Structural Biology, Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
  7. Salam Herojeet Singh

    Structural Biology, Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
  8. Biswajit Pal

    Structural Biology, Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
  9. P Chandra Shekar

    Structural Biology Laboratory, Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    No competing interests declared.
  10. Siddhesh S Kamat

    Department of Biology, Indian Institute of Science Education and Research Pune, Pune, India
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6132-7574
  11. Rajan Sankaranarayanan

    Structural Biology Laboratory, Centre for Cellular and Molecular Biology, Hyderabad, India
    For correspondence
    sankar@ccmb.res.in
    Competing interests
    Rajan Sankaranarayanan, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4524-9953

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

  1. Felix Campelo, Institute of Photonic Sciences, Spain

Publication history

  1. Preprint posted: February 7, 2022 (view preprint)
  2. Received: February 7, 2022
  3. Accepted: June 28, 2022
  4. Accepted Manuscript published: June 29, 2022 (version 1)
  5. 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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  1. Sudipta Mondal
  2. Priyadarshan Kinatukara
  3. Shubham Singh
  4. Sakshi Shambhavi
  5. Gajanan S Patil
  6. Noopur Dubey
  7. Salam Herojeet Singh
  8. Biswajit Pal
  9. P Chandra Shekar
  10. Siddhesh S Kamat
  11. Rajan Sankaranarayanan
(2022)
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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