Accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR). The ATF6 pathway is one of the three major pathways in vertebrates. Although ATF6, a transmembrane-type glycoprotein in the ER, functions as a UPR sensor/transducer, it is an unstable protein with a half-life of approximately 2 h and is constitutively subjected to the ER-associated degradation system with the location of the misfolded part in the ER lumen (ERAD-L). ERAD-L substrates are delivered to the cytosol through the retrotranslocon, which likely contains HRD1 (E3), gp78 (E3), SEL1L (a partner of HRD1), Derlin1/2/3 and Herp1/2. We previously showed that ATF6 represents a novel transmembrane-type ERAD-L substrate requiring both EDEM1/2/3-mediated mannose trimming and SEL1L. Here, by constructing and analyzing chicken DT40 cells deficient in various components of the retrotranslocon, we show that degradation of ATF6 requires Derlin2 or Derlin3 and that Derlin2 and Derlin3 are redundant for ERAD-L of ATF6. We further show that degradation of ATF6 requires Herp1 or Herp2 and that Herp1 and Herp2 are redundant for ERAD-L of ATF6. Furthermore, by investigating five more ERAD-L substrates, we show that SEL1L-dependent substrates require Derlin2/3 and Herp1/2 regardless of their soluble or transmembrane nature. Our results suggest that ERAD-L substrates take several routes to the cytosol. The HRD1-engaged route 1 requires SEL1L, Derlin2 or Derlin3, and Herp1 or Herp2, whereas the HRD1-engaged route 2 does not require them functionally. It remains to be determined whether the latter requires Derlin1 and whether these two routes are compositionally distinct.Key words: endoplasmic reticulum, proteasome, protein degradation, protein misfolding, ubiquitin.

中文翻译：

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SEL1L依赖的底物需要Derlin2 / 3和Herp1 / 2才能实现内质网相关降解。

内质网（ER）中未折叠/错误折叠的蛋白质的积累会激活未折叠的蛋白质应答（UPR）。ATF6途径是脊椎动物的三个主要途径之一。尽管ATF6是ER中的跨膜型糖蛋白，它起着UPR传感器/转导的作用，但它是一种不稳定的蛋白，半衰期约为2小时，并且与ER相关的降解系统组成性地存在于蛋白的位置。 ER内腔（ERAD-L）中的部分折叠错误。ERAD-L底物通过逆转录转运子传递至细胞质，其中可能含有HRD1（E3），gp78（E3），SEL1L（HRD1的伴侣），Derlin1 / 2/3和Herp1 / 2。我们以前表明，ATF6代表一种新型的跨膜型ERAD-L底物，需要EDEM1 / 2/3介导的甘露糖修整和SEL1L。这里，通过构建和分析在反转录转座子的各种成分中缺乏的鸡DT40细胞，我们显示ATF6的降解需要Derlin2或Derlin3，而Derlin2和Derlin3对于ATF6的ERAD-L是多余的。我们进一步表明，ATF6的降解需要Herp1或Herp2，并且Herp1和Herp2对于ATF6的ERAD-L是多余的。此外，通过研究五个以上的ERAD-L底物，我们显示SEL1L依赖的底物需要Derlin2 / 3和Herp1 / 2，无论其可溶性或跨膜性质如何。我们的结果表明，ERAD-L底物采取几种途径到达细胞质。与HRD1接合的路由1需要SEL1L，Derlin2或Derlin3，以及Herp1或Herp2，而与HRD1接合的路由2在功能上不需要它们。