Cellular homeostasis requires selective autophagic degradation of damaged or defective organelles, including the endoplasmic reticulum (ER). Previous studies have shown that specific ER transmembrane receptors recruit LC3 on autophagic membranes by using LC3-interacting domains. In this study, we showed that the N-degron pathway mediates ubiquitin (Ub)-dependent reticulophagy. During this 2-step process, the ER transmembrane E3 ligase TRIM13 undergoes auto-ubiquitination via lysine 63 (K63) linkage chains and acts as a ligand for the autophagic receptor SQSTM1/p62 (sequestosome 1). In parallel, ER-residing molecular chaperones, such as HSPA5/GRP78/BiP, are relocated to the cytosol and conjugated with the amino acid L-arginine (Arg) at the N-termini by ATE1 (arginyltransferase 1). The resulting N-terminal Arg (Nt-Arg) binds the ZZ domain of SQSTM1, inducing oligomerization of SQSTM1-TRIM13 complexes and facilitating recruitment of LC3 on phagophores to the sites of reticulophagy. We developed small molecule ligands to the SQSTM1 ZZ domain and demonstrate that these chemical mimics of Nt-Arg facilitate reticulophagy and autophagic protein quality control of misfolded aggregates in the ER.

中文翻译：

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N-degron途径对网状细胞的调节。

细胞稳态需要受损或有缺陷的细胞器（包括内质网（ER））的选择性自噬降解。先前的研究表明，特定的ER跨膜受体通过使用与LC3相互作用的域在自噬膜上募集LC3。在这项研究中，我们表明N-degron途径介导泛素（Ub）依赖的网状细胞。在此两步过程中，ER跨膜E3连接酶TRIM13通过赖氨酸63（K63）连锁链进行自身泛素化作用，并充当自噬受体SQSTM1 / p62（sequestosome 1）的配体。并行地，驻留ER的分子伴侣，例如HSPA5 / GRP78 / BiP，被重新定位到细胞质中，并通过ATE1（精氨酸转移酶1）在N-末端与氨基酸L-精氨酸（Arg）结合。产生的N末端Arg（Nt-Arg）与SQSTM1的ZZ结构域结合，诱导SQSTM1-TRIM13复合物的寡聚并促进LC3在吞噬细胞上募集到网状细胞的位点。我们开发了SQSTM1 ZZ域的小分子配体，并证明了Nt-Arg的这些化学模拟物有助于网状排列和ER中错误折叠的聚集体的自噬蛋白质量控制。