内质网(ER)在蛋白质的合成和折叠中起着重要的作用,和钙的储存。响应于营养胁迫,ER的体积及其固有蛋白的表达增加。ER-phagy,一种选择性的自噬形式,参与内质网多余成分的降解以恢复体内平衡。到目前为止,已将六种ER驻留蛋白鉴定为ER-吞噬受体。在这项研究中,我们已经确定CALCOCO1是一种新型的ER-phagy受体,用于响应蛋白毒性和营养应激而降解肾小管ER。CALCOCO1是一种同源蛋白,通过LIR和UDS相互作用区(UIR)基序共同作用直接与ATG8蛋白结合。CALCOCO1介导的内质网吞噬需要通过保守的FFAT样基序与内质网膜上的VAMP相关蛋白VAPA和VAPB相互作用。CALCOCO1的耗尽导致内质网扩张和无效的基础自噬通量。与其他内质网吞噬受体不同,CALCOCO1在外周与ER相关。因此,我们将CALCOCO1定义为可溶性内质网吞噬受体。
The endoplasmic reticulum (ER) plays important roles in protein synthesis and folding, and calcium storage. The volume of the ER and expression of its resident proteins are increased in response to nutrient stress. ER-phagy, a selective form of autophagy, is involved in the degradation of the excess components of the ER to restore homeostasis. Six ER-resident proteins have been identified as ER-phagy receptors so far. In this study, we have identified CALCOCO1 as a novel ER-phagy receptor for the degradation of the tubular ER in response to proteotoxic and nutrient stress.
CALCOCO1 is a homomeric protein that binds directly to ATG8 proteins via LIR- and UDS-interacting region (UIR) motifs acting co-dependently.
CALCOCO1-mediated ER-phagy requires interaction with VAMP-associated proteins VAPA and VAPB on the ER membranes via a conserved FFAT-like motif. Depletion of
CALCOCO1 causes expansion of the ER and inefficient basal autophagy flux. Unlike the other ER-phagy receptors,
CALCOCO1 is peripherally associated with the ER. Therefore, we define
CALCOCO1 as a soluble ER-phagy receptor.