SEL1L-dependent Substrates Require Derlin2/3 and Herp1/2 for Endoplasmic Reticulum-associated Degradation.
SEL1L-dependent Substrates Require Derlin2/3 and Herp1/2 for Endoplasmic Reticulum-associated Degradation.
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DOI：
10.1247/csf.17007
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发表时间：
2017-05
影响因子：
1.5
通讯作者：
Takehiro Sugimoto;Satoshi Ninagawa;Shimpei Yamano;Tokiro Ishikawa;T. Okada;S. Takeda;K. Mori
中科院分区：
文献类型：
--
作者：
Takehiro Sugimoto;Satoshi Ninagawa;Shimpei Yamano;Tokiro Ishikawa;T. Okada;S. Takeda;K. Mori
内质网（ER）中未折叠/错误折叠蛋白质的积累会激活未折叠蛋白反应（UPR）。ATF6通路是脊椎动物中的三条主要通路之一。尽管内质网中的跨膜型糖蛋白ATF6作为一种UPR传感器/转导器发挥作用，但它是一种不稳定的蛋白质，半衰期约为2小时，并且在内质网腔（ERAD - L）中错误折叠部分所在位置持续受到内质网相关降解系统的作用。ERAD - L底物通过逆向转运复合体被运输到细胞质中，该复合体可能包含HRD1（E3）、gp78（E3）、SEL1L（HRD1的伴侣）、Derlin1/2/3和Herp1/2。我们之前表明ATF6是一种新型的跨膜型ERAD - L底物，需要EDEM1/2/3介导的甘露糖修剪和SEL1L。在此，通过构建和分析逆向转运复合体各种成分缺失的鸡DT40细胞，我们表明ATF6的降解需要Derlin2或Derlin3，并且Derlin2和Derlin3对于ATF6的ERAD - L是冗余的。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是冗余的。此外，通过研究另外五种ERAD - L底物，我们表明依赖SEL1L的底物无论其可溶性还是跨膜性质都需要Derlin2/3和Herp1/2。我们的结果表明ERAD - L底物有几种进入细胞质的途径。涉及HRD1的途径1需要SEL1L、Derlin2或Derlin3以及Herp1或Herp2，而涉及HRD1的途径2在功能上不需要它们。后者是否需要Derlin1以及这两条途径在组成上是否不同还有待确定。关键词：内质网，蛋白酶体，蛋白质降解，蛋白质错误折叠，泛素
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.