Degradation of the endoplasmic reticulum (ER) via selective autophagy (ER-phagy) is vital for cellular homeostasis. We identify FAM134A/RETREG2 and FAM134C/RETREG3 as ER-phagy receptors, which predominantly exist in an inactive state under basal conditions. Upon autophagy induction and ER stress signal, they can induce significant ER fragmentation and subsequent lysosomal degradation. FAM134A, FAM134B/RETREG1, and FAM134C are essential for maintaining ER morphology in a LC3-interacting region (LIR)-dependent manner. Overexpression of any FAM134 paralogue has the capacity to significantly augment the general ER-phagy flux upon starvation or ER-stress. Global proteomic analysis of FAM134 overexpressing and knockout cell lines reveals several protein clusters that are distinctly regulated by each of the FAM134 paralogues as well as a cluster of commonly regulated ER-resident proteins. Utilizing pro-Collagen I, as a shared ER-phagy substrate, we observe that FAM134A acts in a LIR-independent manner and compensates for the loss of FAM134B and FAM134C, respectively. FAM134C instead is unable to compensate for the loss of its paralogues. Taken together, our data show that FAM134 paralogues contribute to common and unique ER-phagy pathways.

中文翻译：

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FAM134旁系同源物在内质网重塑、内质网自噬和胶原质量控制中的作用

通过选择性自噬 (ER-phagy) 降解内质网 (ER) 对细胞稳态至关重要。我们将 FAM134A/RETREG2 和 FAM134C/RETREG3 鉴定为内质网自噬受体，它们在基础条件下主要以非活性状态存在。在自噬诱导和内质网应激信号下，它们可以诱导显着的内质网断裂和随后的溶酶体降解。FAM134A、FAM134B/RETREG1 和 FAM134C 对于以 LC3 相互作用区 (LIR) 依赖性方式维持 ER 形态至关重要。任何 FAM134 旁系同源物的过表达都能够显着增加饥饿或内质网应激时的内质网自噬通量。FAM134 过表达和敲除细胞系的全局蛋白质组学分析揭示了几个蛋白质簇，这些蛋白质簇受到每个 FAM134 旁系同源物的明显调节，以及一组普遍调节的 ER 驻留蛋白。利用前胶原 I 作为共享的内质网自噬底物，我们观察到 FAM134A 以独立于 LIR 的方式起作用，并分别补偿 FAM134B 和 FAM134C 的损失。相反，FAM134C 无法弥补其旁系同源物的损失。总之，我们的数据显示 FAM134 旁系同源物有助于常见和独特的 ER 吞噬途径。FAM134C 无法弥补其旁系同源物的损失。总之，我们的数据显示 FAM134 旁系同源物有助于常见和独特的 ER 吞噬途径。相反，FAM134C 无法弥补其旁系同源物的损失。总之，我们的数据表明 FAM134 旁系同源物有助于常见和独特的 ER 吞噬途径。