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

doi:10.1038/s41467-022-34450-y

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

Nat Commun. 2022 Nov 10;13(1):6805. doi: 10.1038/s41467-022-34450-y.

Authors

Changnan Wang^#¹, Bingying Wang^#¹, Taruna Pandey¹, Yong Long², Jianxiu Zhang³, Fiona Oh¹, Jessica Sima¹, Ruyin Guo¹, Yun Liu⁴, Chao Zhang⁵, Shaeri Mukherjee⁶, Michael Bassik⁷, Weichun Lin⁴, Huichao Deng⁸, Goncalo Vale⁹, Jeffrey G McDonald⁹, Kang Shen⁸, Dengke K Ma^{10

11}

Affiliations

¹ Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA, USA.
² State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
³ Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA.
⁴ Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁵ Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
⁷ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
⁹ Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁰ Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA, USA. [email protected].
¹¹ Innovative Genomics Institute, University of California, Berkeley, CA, USA. [email protected].

^# Contributed equally.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Caenorhabditis elegans* / genetics
Caenorhabditis elegans* / metabolism
Cell Membrane / metabolism
Endoplasmic Reticulum / metabolism
Humans
Mammals / metabolism
Phospholipids / metabolism
Zebrafish* / genetics
Zebrafish* / metabolism

Substances

Phospholipids

Abstract

Publication types

MeSH terms

Substances

Grants and funding