Lipid transfer proteins mediate the transfer of lipids between organelle membranes, and the loss of function of these proteins has been linked to neurodegeneration. However, the mechanism by which loss of lipid transfer activity leads to neurodegeneration is not understood. In Drosophila photoreceptors, depletion of retinal degeneration B (RDGB), a phosphatidylinositol transfer protein, leads to defective phototransduction and retinal degeneration, but the mechanism by which loss of this activity leads to retinal degeneration is not understood. RDGB is localized to membrane contact sites through the interaction of its FFAT motif with the ER integral protein VAP. To identify regulators of RDGB function in vivo, we depleted more than 300 VAP-interacting proteins and identified a set of 52 suppressors of rdgB The molecular identity of these suppressors indicates a role of novel lipids in regulating RDGB function and of transcriptional and ubiquitination processes in mediating retinal degeneration in rdgB⁹ The human homologs of several of these molecules have been implicated in neurodevelopmental diseases underscoring the importance of VAP-mediated processes in these disorders.

中文翻译：

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揭示膜接触位点脂质转移蛋白功能的潜在机制的遗传筛选。

脂质转移蛋白介导细胞器膜之间的脂质转移，这些蛋白质功能的丧失与神经变性有关。然而，脂质转移活性丧失导致神经变性的机制尚不清楚。在果蝇光感受器中，视网膜变性 B (RDGB)（一种磷脂酰肌醇转移蛋白）的耗竭会导致光转导缺陷和视网膜变性，但这种活性丧失导致视网膜变性的机制尚不清楚。RDGB 通过其 FFAT 基序与 ER 整合蛋白 VAP 的相互作用定位于膜接触位点。为了鉴定体内 RDGB 功能的调节因子，我们耗尽了 300 多个 VAP 相互作用蛋白，并鉴定了一组 52 个rdgB抑制因子。这些抑制因子的分子特性表明新型脂质在调节 RDGB 功能以及转录和泛素化过程中的作用。介导rdgB ⁹中的视网膜变性其中一些分子的人类同源物与神经发育疾病有关，强调了 VAP 介导的过程在这些疾病中的重要性。