Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691 Stockholm, Sweden.
Department of Chemistry and Molecular Biology, University of Gothenburg, 40530 Gothenburg, Sweden.
Dev Cell. 2024 Mar 25;59(6):759-775.e5. doi: 10.1016/j.devcel.2024.01.014. Epub 2024 Feb 13.
Lipid droplets (LDs) are fat storage organelles critical for energy and lipid metabolism. Upon nutrient exhaustion, cells consume LDs via gradual lipolysis or via lipophagy, the en bloc uptake of LDs into the vacuole. Here, we show that LDs dock to the vacuolar membrane via a contact site that is required for lipophagy in yeast. The LD-localized LDO proteins carry an intrinsically disordered region that directly binds vacuolar Vac8 to form vCLIP, the vacuolar-LD contact site. Nutrient limitation drives vCLIP formation, and its inactivation blocks lipophagy, resulting in impaired caloric restriction-induced longevity. We establish a functional link between lipophagy and microautophagy of the nucleus, both requiring Vac8 to form respective contact sites upon metabolic stress. In sum, we identify the tethering machinery of vCLIP and find that Vac8 provides a platform for multiple and competing contact sites associated with autophagy.
脂滴（LDs）是能量和脂质代谢的关键脂肪储存细胞器。当营养物质耗尽时，细胞通过逐渐的脂解或通过脂噬作用（将 LDs 整体摄入液泡）来消耗 LDs。在这里，我们表明 LDs 通过一个接触位点与液泡膜对接，该接触位点对于酵母中的脂噬作用是必需的。LD 定位的 LDO 蛋白携带一个固有无序区域，该区域可直接与液泡 Vac8 结合形成 vCLIP，即液泡-LD 接触位点。营养物质限制驱动 vCLIP 的形成，其失活会阻止脂噬作用，从而导致热量限制诱导的寿命延长受损。我们建立了脂噬作用与核微自噬之间的功能联系，这两者都需要 Vac8 在代谢应激下形成各自的接触位点。总之，我们确定了 vCLIP 的系泊机制，并发现 Vac8 为与自噬相关的多个竞争接触位点提供了一个平台。
