Department of Cell Biology, Blavatnik Institute of Harvard Medical School, Boston, MA 02115, USA.
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Mol Cell. 2019 Jun 6;74(5):891-908.e10. doi: 10.1016/j.molcel.2019.03.034. Epub 2019 Apr 18.
Cells respond to nutrient stress by trafficking cytosolic contents to lysosomes for degradation via macroautophagy. The endoplasmic reticulum (ER) serves as an initiation site for autophagosomes and is also remodeled in response to nutrient stress through ER-phagy, a form of selective autophagy. Quantitative proteome analysis during nutrient stress identified an unstudied single-pass transmembrane ER protein, TEX264, as an ER-phagy receptor. TEX264 uses an LC3-interacting region (LIR) to traffic into ATG8-positive puncta that often initiate from three-way ER tubule junctions and subsequently fuse with lysosomes. Interaction and proximity biotinylation proteomics identified a cohort of autophagy regulatory proteins and cargo adaptors located near TEX264 in an LIR-dependent manner. Global proteomics and ER-phagy flux analysis revealed the stabilization of a cohort of ER proteins in TEX264 cells during nutrient stress. This work reveals TEX264 as an unrecognized ER-phagy receptor that acts independently of other candidate ER-phagy receptors to remodel the ER during nutrient stress.
细胞通过巨自噬将细胞质内容物运送到溶酶体进行降解，从而对营养压力做出反应。内质网（ER）是自噬体的起始部位，并且通过 ER 自噬（一种选择性自噬形式）对营养压力做出响应而被重塑。在营养压力期间进行的定量蛋白质组分析鉴定了一种未被研究的单次跨膜 ER 蛋白 TEX264 作为 ER 自噬受体。TEX264 使用 LC3 相互作用区域（LIR）将内容物运送到 ATG8 阳性斑点中，这些斑点通常从三向 ER 管接头开始，并随后与溶酶体融合。相互作用和接近生物素标记蛋白质组学鉴定了一组位于 TEX264 附近的自噬调节蛋白和货物衔接子，这些蛋白以 LIR 依赖性方式存在。全局蛋白质组学和 ER 自噬通量分析显示，在营养压力下，TEX264 细胞中的一组 ER 蛋白稳定。这项工作揭示了 TEX264 作为一种未被识别的 ER 自噬受体，它在营养压力期间独立于其他候选 ER 自噬受体起作用，以重塑 ER。
