Abstract
Regulating nuclear histone balance is essential for survival, yet in early Drosophila melanogaster embryos many regulatory strategies employed in somatic cells are unavailable. Previous work had suggested that lipid droplets (LDs) buffer nuclear accumulation of the histone variant H2Av. Here, we elucidate the buffering mechanism and demonstrate that it is developmentally controlled. Using live imaging, we find that H2Av continuously exchanges between LDs. Our data suggest that the major driving force for H2Av accumulation in nuclei is H2Av abundance in the cytoplasm and that LD binding slows nuclear import kinetically, by limiting this cytoplasmic pool. Nuclear H2Av accumulation is indeed inversely regulated by overall buffering capacity. Histone exchange between LDs abruptly ceases during the midblastula transition, presumably to allow canonical regulatory mechanisms to take over. These findings provide a mechanistic basis for the emerging role of LDs as regulators of protein homeostasis and demonstrate that LDs can control developmental progression.
Highlights
Protein homeostasis is essential for cell survival and function, and it is controlled via a plethora of synergizing mechanisms, including protein synthesis, folding, transport, and degradation
Previous work demonstrated a role for lipid droplets (LDs) as histone stores: when new histone biosynthesis is compromised, histones on LDs are necessary for proper embryonic development (Li et al, 2012), presumably to package chromatin because such embryos die with phenotypes reminiscent of severe lack of histones
We provide evidence that for the variant histone H2Av in early Drosophila embryos the dominant step for regulating histone incorporation is not histone abundance per se, but post-translational regulation of available H2Av protein via buffering by LDs: in these embryos, LDs transiently sequester excess H2Av, effectively depleting the H2Av pool that is readily available for nuclear import and chromatin deposition (Figure 5A)
Summary
Protein homeostasis is essential for cell survival and function, and it is controlled via a plethora of synergizing mechanisms, including protein synthesis, folding, transport, and degradation. LDs are implicated in the refolding of certain damaged proteins in yeast and the assembly of viral protein complexes in mammalian cells. In Drosophila embryos, LDs store large amounts of specific histones for use later in development; and in mammals, LDs promote the degradation of certain ER proteins. We take advantage of the possibly best characterized example of protein handling via LDs, namely their role in histone metabolism in Drosophila embryos (Cermelli et al, 2006; Li et al, 2014, Li et al, 2012).
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