Lilley Brendan N, Ploegh Hidde L
Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14296-301. doi: 10.1073/pnas.0505014102. Epub 2005 Sep 26.
Polypeptides that fail to pass quality control in the endoplasmic reticulum (ER) are dislocated from the ER membrane to the cytosol where they are degraded by the proteasome. Derlin-1, a member of a family of proteins that bears homology to yeast Der1p, was identified as a factor that is required for the human cytomegalovirus US11-mediated dislocation of class I MHC heavy chains from the ER membrane to the cytosol. Derlin-1 acts in concert with the AAA ATPase p97 to remove dislocation substrate proteins from the ER membrane, but it is unknown whether other factors aid Derlin-1 in its function. Mammalian genomes encode two additional, related proteins (Derlin-2 and Derlin-3). The similarity of the mammalian Derlin-2 and Derlin-3 proteins to yeast Der1p suggested that these as-yet-uncharacterized Derlins also may play a role in ER protein degradation. We demonstrate here that Derlin-2 is an ER-resident protein that, similar to Derlin-1, participates in the degradation of proteins from the ER. Furthermore, we show that Derlin-2 forms a robust multiprotein complex with the p97 AAA ATPase as well as the mammalian orthologs of the yeast Hrd1p/Hrd3p ubiquitin-ligase complex. The data presented here define a set of interactions between proteins involved in dislocation of misfolded polypeptides from the ER.
未能通过内质网（ER）质量控制的多肽会从ER膜移位至胞质溶胶，在那里它们会被蛋白酶体降解。Derlin-1是一种与酵母Der1p具有同源性的蛋白质家族成员，被鉴定为人类巨细胞病毒US11介导的I类MHC重链从ER膜移位至胞质溶胶所必需的因子。Derlin-1与AAA ATP酶p97协同作用，从ER膜上去除移位底物蛋白，但尚不清楚是否有其他因子协助Derlin-1发挥其功能。哺乳动物基因组编码另外两种相关蛋白（Derlin-2和Derlin-3）。哺乳动物Derlin-2和Derlin-3蛋白与酵母Der1p的相似性表明，这些尚未被表征的Derlin蛋白也可能在ER蛋白降解中发挥作用。我们在此证明，Derlin-2是一种驻留在内质网的蛋白，与Derlin-1类似，参与内质网蛋白的降解。此外，我们表明Derlin-2与p97 AAA ATP酶以及酵母Hrd1p/Hrd3p泛素连接酶复合体的哺乳动物直系同源物形成了一个强大的多蛋白复合体。本文提供的数据定义了一组参与错误折叠多肽从内质网移位的蛋白质之间的相互作用。
