Cells can withstand cold when they make their plasma membrane more fluid using unsaturated lipids. In the model organism Caenorhabditis elegans, cold-induced phospholipid supply is managed by a huge protein forming a remarkable direct tunnel between the endoplasmic reticulum and the plasma membrane, a study shows . Studying the biochemistry of this protein and its relatives in other species, and how it transports lipids, could lead to new treatments for disorders of fatty acid metabolism.
Transport of Unsaturated Fatty Acids
Under cold conditions, cell membranes get stiffer. To maintain functionality, genes are activated in the cells to produce more phospholipids containing unsaturated fatty acids. Unsaturation increases disorder, in turn raising the fluidity in the plasma membrane. However, to achieve this, unsaturated phospholipids, which are synthesized in the endoplasmic reticulum, have to be transported to the plasma membrane.
One might expect this transport to take place through vesicle secretion. It is textbook knowledge that the endoplasmic reticulum releases its products in the form of lipid vesicles, which integrate in the membrane of the target organelle for further processing. Other modes of transport from the endoplasmic reticulum are less understood.
However, this is about to change. Searching for genes that upregulate unsaturated fatty acid synthesis in the nematode Caenorhabditis elegans, researchers led by biophysicist Dengke Ma from the University of California, San Francisco, USA, have identified a “molecular highway bridge” that directly connects the endoplasmic reticulum with the plasma membrane. This bridge, or more precisely tunnel, is formed by a huge protein called LPD-3.
Ma and his team characterized the LPD-3 protein as a megaprotein having a remarkable length of 4018 amino acid residues. Performing AI-based structure prediction, they found it folds to form a 30-nanometers rod – roughly the size of a small virus particle. Within the protein, twisted beta sheets form a hydrophobic tunnel stretching the entire length of the rod. The researchers also identified a hydrophobic extension at one end and an amphiphilic extension at the other and suggest these are the sites of contact with the endoplasmic reticulum and the plasma membrane.
Using fluorescence imaging, the researchers located LPD-3 in the nematode’s intestine, where it was expressed in the endoplasmic reticulum of the intestinal cells. They also confirmed it was involved in enriching the plasma membrane with phospholipids to ensure its integrity. In addition, mutants with defective LPD-3 genes took longer to develop to reach their final larvae states, while adult nematodes were more sensitive to cold and freezing. The researchers also showed that LPD-3-depleted membranes were leaky and showed less plasticity.
Conserved Protein Family
The LPD-3 protein is not entirely unknown, though. The researchers emphasize that it belongs to a highly evolutionarily conserved protein family known from many model organisms such as fruit flies, zebra fish, mice, and humans. All gene products seem to play important roles in lipid metabolism, helping yeast cells adapt to the cold and regulating synaptic functions in fruit flies. The researchers thus describe LPD-3 as a new class of lipid transporters that is “critical for directed non-vesicular trafficking of lipids across different organelle membranes.”
Defective genes can have crucial implications. In humans, mutations in the human orthologue BLTP1 cause a rare, but severe genetic disorder called Alkuraya-Kucinskas syndrome. Children having this syndrome have impaired cardiovascular and neuronal development, cannot speak or walk, and often do not survive infancy.
In this context, it is of particular interest that Ma and his colleagues discovered how to treat functional defects of LPD-3. Supplying LPD-3 mutants of C. elegans with additional phospholipids rescued them from developmental delay and reinstated their cold and freezing resilience. This observation could point to possible applications in medical research and provide new approaches in lipid metabolism research.
 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, KangShen, Dengke K. Ma, A conserved megaprotein-based molecular bridge critical for lipid trafficking and cold resilience, Nat. Commun. 2022, 13:6805. https://doi.org/10.1038/s41467-022-34450-y