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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.

Due to antimicrobial resistance, current treatments for tuberculosis (TB) are very limited and have very low efficacy. Existing therapeutics are inadequate for the ongoing epidemic of drug resistance TB. The evolutionary push of mutations created is destabilizing global TB control, thereby needing new novel therapies for treatment and screening purposes. In this paper, we propose two potential pathways that target TB through IFN-I signaling and the AhR pathway which allows for more accurate and efficient early screening of TB. Targeting these pathways impacts TB outcome by increasing treatment efficacy and strengthening host defense. IFN-I signaling and the AHR pathway can be seen as potential targets for host directed therapies.