Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, CO, USA.
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, CO, USA
Life Sci Alliance. 2019 May 17;2(3). doi: 10.26508/lsa.201900340. Print 2019 Jun.
Autophagy is a conserved system that adapts to nutrient starvation, after which proteins and organelles are degraded to recycle amino acids in response to starvation. Recently, the ER was added to the list of targets of autophagic degradation. Autophagic degradation pathways of bulk ER and the specific proteins sorted through the ER are considered key mechanisms in maintaining ER homeostasis. Four ER-resident proteins (FAM134B, CCPG1, SEC62, and RTN3) have been identified as ER-resident cargo receptors, which contain LC3-interacting regions. In this study, we identified an N-terminal-truncated isoform of FAM134B (FAM134B-2) that contributes to starvation-induced ER-related autophagy. Hepatic FAM134B-2 but not full-length FAM134B (FAM134B-1) is expressed in a fed state. Starvation drastically induces FAM134B-2 but no other ER-resident cargo receptors through transcriptional activation by C/EBPβ. C/EBPβ overexpression increases FAM134B-2 recruitment into autophagosomes and lysosomal degradation. FAM134B-2 regulates lysosomal degradation of ER-retained secretory proteins such as ApoCIII. This study demonstrates that the C/EBPβ-FAM134B-2 axis regulates starvation-induced selective ER-phagy.
自噬是一种适应营养饥饿的保守系统，在饥饿时，蛋白质和细胞器被降解以回收氨基酸。最近，内质网被添加到自噬降解的靶标列表中。内质网的 bulk ER 自噬降解途径和通过内质网分拣的特定蛋白质被认为是维持内质网稳态的关键机制。已经鉴定出四种内质网驻留蛋白（FAM134B、CCPG1、SEC62 和 RTN3）作为内质网驻留货物受体，它们包含 LC3 相互作用区域。在这项研究中，我们鉴定出 FAM134B 的一种 N 端截断异构体（FAM134B-2），它有助于饥饿诱导的与内质网相关的自噬。在进食状态下，肝脏中表达的是 FAM134B-2 而不是全长 FAM134B（FAM134B-1）。通过 C/EBPβ 的转录激活，饥饿会强烈诱导 FAM134B-2 而不是其他内质网驻留货物受体。C/EBPβ 的过表达增加了 FAM134B-2 被招募到自噬体和溶酶体降解中的程度。FAM134B-2 调节 ER 保留的分泌蛋白（如 ApoCIII）的溶酶体降解。这项研究表明，C/EBPβ-FAM134B-2 轴调节饥饿诱导的选择性内质网自噬。
