Tiny sacs of lipids long thought to merely act as floating cellular pantries have an unexpected function, according to a new study (Science 2020, DOI: 10.1126/science.aay8085). The lipid droplets can trap attacking pathogens, luring them with free food, then killing them with antimicrobial proteins.
Lipid droplets consist of triacylglycerols and cholesteryl esters wrapped inside membrane sacs. When the cell needs a boost, these lipids can be metabolized by the mitochondria, the cell’s energy-generating organelles. Researchers know that these organelles attract pathogens—but they have generally believed that microbial invaders hijack them for energy.
There have been some hints that lipid droplets may play an antibacterial role, but this study clearly pins it down, says James Olzmann, a biochemist at the University of California, Berkeley, who was not involved in the work. The research “provides compelling evidence that lipid droplets are part of a powerful cellular defense mechanism,” he says.
To uncover the details of this mechanism, researchers from the University of Barcelona first exposed mice to lipopolysaccharides, bacterial membrane molecules that induce an immune response. Then, they isolated lipid droplets from those animals and uninfected ones and added them to a dish of Escherichia coli. Both sets of droplets killed some of the bacteria, but the lipid droplets from the infected mice were more potent. Similarly, human white blood cells carrying extra lipid droplets were better at killing E coli than unmodified white blood cells. “It was a very simple experiment,” says Marta Bosch, a cell biologist at the University of Barcelona who worked on the lipid-droplet research with her postdoc advisor Albert Pol.
Though simple, this experiment clearly demonstrates that the lipid droplets are related to an immune response. Bosch and her colleagues then went on to study that immune response in more detail, using mass spectrometry to identify the proteins attached to the outside of the lipid droplets. Close to 700 proteins changed their expression levels in the cells from infected mice. Bosch and her colleagues’ modelling work suggests that these organelles are hubs of immune activity, and additional experiments showed that some of these immune proteins associate with lipid droplets and have antimicrobial properties.
Lipid droplets normally associate with mitochondria. But during an infection, these organelles seem to help switch cells into a bacteria-fighting metabolic mode by uncoupling themselves from the mitochondria so that they can then swarm the infecting microbes. In infected cells, a drop in expression of a protein called PLIN5 helps promote this uncoupling. Meanwhile, a boost in expression of another protein, PLIN2, pulled immune proteins toward the organelles.
“What we found here is that the lipid droplet coordinates this defense system, targeting known antimicrobials toward this organelle that the pathogen is going to be attracted to,” Bosch says. Creating antimicrobial drugs that act at the lipid droplet, where pathogens congregate, may be a way to make such drugs more efficient, she says.
“The sheer scale” of lipid droplets’ role in immunity is “unexpected,” says Joachim Füllekrug, a biochemist at Heidelberg University who was not involved in the study. Considering that all cell types can make them, these organelles “may have originated in evolution just as a means for storing surplus molecules with high energy content,” he speculates. And there may be more surprises ahead as researchers continue to identify other functions for lipid droplets.