Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland.
J Cell Biol. 2010 Jan 25;188(2):223-35. doi: 10.1083/jcb.200910042.
Sophisticated quality control mechanisms prolong retention of protein-folding intermediates in the endoplasmic reticulum (ER) until maturation while sorting out terminally misfolded polypeptides for ER-associated degradation (ERAD). The presence of structural lesions in the luminal, transmembrane, or cytosolic domains determines the classification of misfolded polypeptides as ERAD-L, -M, or -C substrates and results in selection of distinct degradation pathways. In this study, we show that disposal of soluble (nontransmembrane) polypeptides with luminal lesions (ERAD-L(S) substrates) is strictly dependent on the E3 ubiquitin ligase HRD1, the associated cargo receptor SEL1L, and two interchangeable ERAD lectins, OS-9 and XTP3-B. These ERAD factors become dispensable for degradation of the same polypeptides when membrane tethered (ERAD-L(M) substrates). Our data reveal that, in contrast to budding yeast, tethering of mammalian ERAD-L substrates to the membrane changes selection of the degradation pathway.
复杂的质量控制机制可以延长内质网 (ER) 中蛋白质折叠中间体的保留时间，直到成熟，同时分拣出终末错误折叠的多肽进行内质网相关降解 (ERAD)。腔、跨膜或胞质域中结构损伤的存在决定了错误折叠多肽被分类为 ERAD-L、-M 或 -C 底物，并导致选择不同的降解途径。在这项研究中，我们表明，具有腔损伤的可溶性（非跨膜）多肽（ERAD-L(S) 底物）的处理严格依赖于 E3 泛素连接酶 HRD1、相关的货物受体 SEL1L 和两种可互换的 ERAD 凝集素 OS-9 和 XTP3-B。当这些 ERAD 因子被膜固定（ERAD-L(M) 底物）时，它们对于降解相同的多肽变得可有可无。我们的数据表明，与芽殖酵母不同，哺乳动物 ERAD-L 底物与膜的连接改变了降解途径的选择。
