美国哈佛医学院J. Wade Harper研究团队发现，营养压力下的蛋白质组普查揭示高尔基自噬膜受体。该研究于2023年9月27日在线发表于国际一流学术期刊《自然》。

研究人员利用正交蛋白质组学策略提供了哺乳动物细胞在营养应激过程中自噬货物的空间蛋白质组普查。研究人员发现巨自噬对回收膜结合细胞器（主要是高尔基体和ER）具有选择性。通过对自噬货物进行优先排序，研究人员发现膜嵌入蛋白YIPF3和YIPF4是高尔基吞噬作用的受体。在营养应激过程中，YIPF3和YIPF4通过LIR基序与ATG8相互作用，并被动员到自噬体中，自噬体在一个需要典型自噬机制的过程中被运送到溶酶体。缺乏YIPF3或YIPF4的细胞在营养应激时会选择性地缺乏消除特定高尔基体膜蛋白的能力。

此外，YIPF3/4在体外干细胞向神经细胞系程序转换过程中的高尔基体重塑过程中也发挥着类似的作用。总之，这项研究揭示了在营养应激依赖性蛋白质组重塑过程中膜蛋白货物的优先顺序，并确定了一种需要膜嵌入受体的意想不到的高尔基体重塑途径。

研究人员表示，在营养应激期间，巨自噬作用会降解细胞大分子，从而提供生物合成的基石，同时重塑蛋白质组。虽然负责启动巨自噬的机制已被很好地描述，但人们对单个蛋白质、蛋白质复合物和细胞器被选择进行自噬降解的程度以及潜在的靶向机制的了解还很有限。

附：英文原文

Title: Proteome census upon nutrient stress reveals Golgiphagy membrane receptors

Author: Hickey, Kelsey L., Swarup, Sharan, Smith, Ian R., Paoli, Julia C., Miguel Whelan, Enya, Paulo, Joao A., Harper, J. Wade

Issue&Volume: 2023-09-27

Abstract: During nutrient stress, macroautophagy degrades cellular macromolecules, thereby providing biosynthetic building blocks while simultaneously remodeling the proteome1,2. While machinery responsible for initiation of macroautophagy is well characterized3,4, our understanding of the extent to which individual proteins, protein complexes and organelles are selected for autophagic degradation, and the underlying targeting mechanisms is limited. Here, we use orthogonal proteomic strategies to provide a spatial proteome census of autophagic cargo during nutrient stress in mammalian cells. We find that macroautophagy has selectivity for recycling membrane-bound organelles (principally Golgi and ER). Through autophagic cargo prioritization, we identify a complex of membrane-embedded proteins, YIPF3 and YIPF4, as receptors for Golgiphagy. During nutrient stress, YIPF3 and YIPF4 interact with ATG8s via LIR motifs and are mobilized into autophagosomes that traffic to lysosomes in a process that requires the canonical autophagic machinery. Cells lacking YIPF3 or YIPF4 are selectively defective in elimination of a specific cohort of Golgi membrane proteins during nutrient stress. Moreover, YIPF3/4 play an analogous role in Golgi remodeling during programmed conversion of stem cells to the neuronal lineage in vitro. Collectively, this study reveals prioritization of membrane protein cargo during nutrient stress-dependent proteome remodeling and identifies an unanticipated Golgi remodeling pathway requiring membrane-embedded receptors.

DOI: 10.1038/s41586-023-06657-6

Source: https://www.nature.com/articles/s41586-023-06657-6