TY - JOUR
T1 - A conserved megaprotein-based molecular bridge critical for lipid trafficking and cold resilience
AU - Wang, Changnan
AU - Wang, Bingying
AU - Pandey, Taruna
AU - Long, Yong
AU - Zhang, Jianxiu
AU - Oh, Fiona
AU - Sima, Jessica
AU - Guo, Ruyin
AU - Liu, Yun
AU - Zhang, Chao
AU - Mukherjee, Shaeri
AU - Bassik, Michael
AU - Lin, Weichun
AU - Deng, Huichao
AU - Vale, Goncalo
AU - McDonald, Jeffrey G.
AU - Shen, Kang
AU - Ma, Dengke K.
N1 - Funding Information:
Some strains were provided by Drs. Barth Grant, Rosa E. Navarro González, and Caenorhabditis Genetics Center (CGC), which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). The work was supported by NIH grant 1R35GM139618, UCSF PBBR New Frontier Research (NFR) and the Packard Fellowship in Science and Engineering (D.K.M).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-34450-y
DO - 10.1038/s41467-022-34450-y
M3 - Article
C2 - 36357390
AN - SCOPUS:85141639482
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6805
ER -