PDF(Pubmed)
Abstract：
The endoplasmic reticulum (ER) produces proteins destined to organelles of the endocytic and secretory pathways, the plasma membrane, and the extracellular space. While native proteins are transported to their intra- or extracellular site of activity, folding-defective polypeptides are retro-translocated across the ER membrane into the cytoplasm, poly-ubiquitylated and degraded by 26 S proteasomes in a process called ER-associated degradation (ERAD). Large misfolded polypeptides, such as polymers of alpha1 antitrypsin Z (ATZ) or mutant procollagens, fail to be dislocated across the ER membrane and instead enter ER-to-lysosome-associated degradation (ERLAD) pathways. Here, we show that pharmacological or genetic inhibition of ERAD components, such as the α1,2-mannosidase EDEM1 or the OS9 ERAD lectins triggers the delivery of the canonical ERAD clients Null Hong Kong (NHK) and BACE457Δ to degradative endolysosomes under control of the ER-phagy receptor FAM134B and the LC3 lipidation machinery. Our results reveal that ERAD dysfunction is compensated by the activation of FAM134B-driven ERLAD pathways that ensure efficient lysosomal clearance of orphan ERAD clients.
摘要：
内质网（ER）产生的蛋白质注定的细胞器的内吞和分泌途径，质膜，和细胞外空间。虽然天然蛋白质被转运到它们的细胞内或细胞外活性位点，折叠缺陷多肽通过内质网膜向后转位到细胞质中，在称为ER相关降解（ERAD）的过程中，多聚泛素化并被26S蛋白酶体降解。大的错误折叠的多肽，例如α1抗胰蛋白酶Z（ATZ）或突变型原蛋白的聚合物，未能在ER膜上脱位，而是进入ER到溶酶体相关降解（ERLAD）途径。这里,我们表明ERAD成分的药理或遗传抑制，例如α1,2-甘露糖苷酶EDEM1或OS9ERAD凝集素触发了规范的ERAD客户端NullHongKong（NHK）和BACE457Δ在ER-phagy受体FAM134B和LC3脂化机制的控制下将降解内溶酶体。我们的结果表明，通过激活FAM134B驱动的ERLAD途径来补偿ERAD功能障碍，从而确保孤儿ERAD客户的有效溶酶体清除。
