The endoplasmic reticulum (ER) is the largest membrane-bound organelle in eukaryotic cells and plays critical roles in diverse processes in metabolism, signaling and intracellular organization. In response to stress stimuli such as nutrient deprivation, accumulation of misfolded proteins or exposure to chemicals, the ER increases in size through upregulated synthesis of its components to counteract the stress. To restore physiological size, the excess ER components are continuously dismantled and degraded by reticulophagy, a form of autophagy that targets, via adaptor molecules called reticulophagy receptors, specific ER portions to the lysosome for degradation. Previous studies have identified several ER resident proteins as reticulophagy receptors. In a recent study, we identified CALCOCO1 as a soluble reticulophagy receptor for the degradation of tubular ER in response to proteotoxic and starvation-induced stress. On the ER membrane, CALCOCO1 interacts with VAPA and VAPB via a FFAT-like motif and recruits autophagy machinery by binding directly to Atg8-family proteins via LIR and UDS interacting region (UIR) motifs acting co-dependently. Depletion of CALCOCO1 in cultured cells led to an impaired ER degradation during stress.

内质网 (ER) 是真核细胞中最大的膜结合细胞器，在代谢、信号传导和细胞内组织的不同过程中起着关键作用。响应压力刺激，如营养缺乏、错误折叠蛋白质的积累或暴露于化学物质，ER 通过上调其成分的合成来增加大小，以抵消压力。为了恢复生理大小，多余的 ER 成分被网状吞噬不断分解和降解，网状吞噬是一种自噬形式，通过称为网状吞噬受体的衔接分子将特定的 ER 部分靶向溶酶体进行降解。以前的研究已经确定了几种内质网驻留蛋白作为网状吞噬受体。在最近的一项研究中，我们将 CALCOCO1 鉴定为可溶性网状吞噬受体，用于响应蛋白毒性和饥饿诱导的压力而降解管状内质网。在 ER 膜上，CALCOCO1 通过 FFAT 样基序与 VAPA 和 VAPB 相互作用，并通过 LIR 和 UDS 相互作用区 (UIR) 基序直接结合 Atg8 家族蛋白来招募自噬机制。培养细胞中 CALCOCO1 的消耗导致应激期间内质网降解受损。