A conserved megaprotein-based molecular bridge critical for lipid trafficking and cold resilience

Changnan Wang, Bingying Wang, Taruna Pandey, Yong Long, Jianxiu Zhang, Fiona Oh, Jessica Sima, Ruyin Guo, Yun Liu, Chao Zhang, Shaeri Mukherjee, Michael Bassik, Weichun Lin, Huichao Deng, Goncalo Vale, Jeffrey G. McDonald, Kang Shen, Dengke K. Ma

Research output: Contribution to journalArticlepeer-review


Cells adapt to cold by increasing levels of unsaturated phospholipids and membrane fluidity through conserved homeostatic mechanisms. Here we report an exceptionally large and evolutionarily conserved protein LPD-3 in C. elegans that mediates lipid trafficking to confer cold resilience. We identify lpd-3 mutants in a mutagenesis screen for genetic suppressors of the lipid desaturase FAT-7. LPD-3 bridges the endoplasmic reticulum (ER) and plasma membranes (PM), forming a structurally predicted hydrophobic tunnel for lipid trafficking. lpd-3 mutants exhibit abnormal phospholipid distribution, diminished FAT-7 abundance, organismic vulnerability to cold, and are rescued by Lecithin comprising unsaturated phospholipids. Deficient lpd-3 homologues in Zebrafish and mammalian cells cause defects similar to those observed in C. elegans. As mutations in BLTP1, the human orthologue of lpd-3, cause Alkuraya-Kucinskas syndrome, LPD-3 family proteins may serve as evolutionarily conserved highway bridges critical for ER-associated non-vesicular lipid trafficking and resilience to cold stress in eukaryotic cells.

Original languageEnglish (US)
Article number6805
JournalNature communications
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)


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