Research Overview
Lipid droplets as protein sequestration sites
(Left) Fluorescence and bright-light images of centrifuged embryos stained for histone H2A (green). In the wild type, H2A is highly enriched on the fluffy top layer, which represents lipid droplets. In embryos lacking Jabba, H2A is entirely absent from the lipid-droplet layer.
(Right) Working model for how Jabba acts as the histone anchor on lipid droplets.
Lipid droplets have been extensively characterized as fat storage organelles, and they play critical roles in lipid metabolism and energy homeostasis. In many systems, when living embryos are centrifuged, it is possible to separate organelles by density in vivo. This technique reveals that certain histones are sequestered on lipid droplets.proteomic analysis of purified lipid droplets has uncovered dozens, if not hundreds, of candidate lipid-droplet proteins, including many proteins from other cellular compartments. Determining which of these proteins are bona-fide droplet proteins and which are simply contaminants is a continuing challenge for the field.
We found that in early Drosophila embryos certain histones are among the most abundant lipid-droplet proteins (Cermelli et al., 2006). The image above shows how we used in-vivo centrifugation of embryos to demonstrate that histones are indeed present on droplets in vivo. These studies lead to the proposal that lipid droplets have a general role as sites for protein sequestration (Welte, 2007).
We recently were able to critically test this idea. We identified the novel protein Jabba as the histone anchor on lipid droplets (Li et al., 2012). In the absence of Jabba, the otherwise droplet-bound histones are absent from the embryo, likely because they are no longer shielded from degradation. Jabba mutants are synthetically lethal with mutations that slightly impair histone biosynthesis. These observations suggest that the droplet-bound histones provide one source of histones to support early development and that lipid droplets can indeed store proteins for later use (Li et al., 2012). We have now discovered that lipid droplets not only act as long-term storage sites, but also as short-term buffers that control the ratio of various histones in the nucleus (Li et al., 2014).
Because in vitro histones have potent antibacterial activity, it raises the intriguing possibility that organism can use the droplet-bound histone reservoir as a defense mechanism. Consistent with this notion, Jabba mutant embryos fail to restrict the growth of experimentally introduced bacteria and are much more sensitive to killing by bacterial pathogens (Anand et al., 2012).
These studies on the functional importance of histones on lipid droplets have generated lots of excitement in the research community, including highlights in Current Biology, eLife, Nature Reviews Molecular Cell Biology, Nature Reviews Microbiology, The Scientist, and multiple recommendations by Faculty of 1000.
Ongoing projects:
- Structure-function analysis for Jabba
- Dynamics of Jabba and histones
- How do lipid droplets buffer fluctuations in histone availability?
For other projects in the laboratory, please check out the links below: