Membrane Phospholipid Asymmetry Counters the Adverse Effects of Sterol Overloading in the Golgi Membrane of Drosophila

Abstract

Cholesterol and phospholipids serve as structural and functional components of cellular membranes in all eukaryotes. Heterogeneity in cholesterol and phospholipid content both within and between different organelles is an important characteristic of eukaryotic membranes. How this heterogeneity is achieved and orchestrated to maintain proper cellular physiology remains poorly understood. We previously found that overexpression of the Drosophila oxysterol-binding protein (OSBP) leads to sterol accumulation in the Golgi apparatus. Here, we show that Osbp overexpression in a set of neuroendocrine neurons compromises the function of the Golgi apparatus. It impairs trafficking of the neuropeptide bursicon and results in post-eclosion behavior defects characterized by unexpanded wings. We performed a genetic screen to identify modifiers that suppress the unexpanded wing phenotype. A putative phospholipid flippase-encoding gene, CG33298, was validated, suggesting that a membrane-asymmetry-directed mechanism balances cholesterol chaos within the Golgi membranes. Since the functional connection between cholesterol metabolism and the activity of phospholipid flippase has been implicated in studies in yeast and worms, our findings here support an evolutionarily conserved causal link between cholesterol homeostasis and phospholipid asymmetry that maintains normal cellular physiology.

A P4-ATPase subunit of the Cdc50 family plays a role in iron acquisition and virulence inCryptococcus neoformans

“…We hypothesize that the contribution of Cdc50 to flippase activity in establishing and maintaining phospholipid asymmetry is important to the balance between ergosterol and phospholipids. This balance has been demonstrated in S. cerevisiae and Drosophila melanogaster through the characterization of oxysterol-binding proteins (Ma, Liu, & Huang, 2012;Misu et al, 2003;Muthusamy et al, 2009b). These results focus attention on the potential to target the balance with antifungal drugs, and synergistic activity between curcumin and fluconazole has already been described in C. albicans (Garcia-Gomes, Curvelo, Soares, & Ferreira-Pereira, 2012;Sharma, Manoharlal, Negi, & Prasad, 2010).…”

“…This balance has been demonstrated in S . cerevisiae and Drosophila melanogaster through the characterization of oxysterol‐binding proteins (Ma, Liu, & Huang, ; Misu et al, ; Muthusamy et al, ). These results focus attention on the potential to target the balance with antifungal drugs, and synergistic activity between curcumin and fluconazole has already been described in C .…”

WITHDRAWN: The Fundamental And Pathological Importance Of Oxysterol Binding Protein And Its Related Proteins

“…Studies in Caenorhabditis elegans and Drosophilia melanogaster revealed a similar functional redundancy. Furthermore, these studies indicated that as well as their role in cell growth OSBP/ORPs are also essential for lipid homeostasis in cells that lack the ability to synthesise sterol themselves (20,21).…”

Using natural variation in Drosophila to discover previously unknown endoplasmic reticulum stress genes

“…Some of these candidates have functions not previously associated with ER stress, but others function in processes known to be important to the ER stress response. Examples of the latter include Golgi function (CG33298 and CG15611) (34,35), lipid metabolism (CG12428, bgm, Egm, CG9518, RdgA, and CG5162) (36)(37)(38)(39)(40)(41), and oxidative stress (CG11594, CG9003, RunxA, and CG11873) (23,42). In particular, an associated SNP 65 bp downstream of eIF-2β, the beta subunit of the eIF2 translation initiation factor (43), is particularly interesting.…”