Crawshaw Samuel G, Cross Benedict C S, Wilson Cornelia M, High Stephen
Faculty of Life Sciences, University of Manchester, Manchester, UK.
Mol Membr Biol. 2007 Mar-Apr;24(2):113-20. doi: 10.1080/09687860600988727.
The endoplasmic reticulum (ER) is a major site of protein synthesis in eukaryotes. Newly synthesized proteins are monitored by a process of quality control, which removes misfolded or unassembled polypeptides from the ER for degradation by the proteasome. This requires the retrotranslocation of the misfolded proteins from the ER lumen into the cytosol via a pathway that, for some substrates, involves members of the recently discovered Derlin family. The Derlin-1 isoform is present as a dimer in the ER, and we now show that its dimerization is modulated by ER stress. Three distinct types of chemically-induced ER stress substantially reduce the levels of Derlin-1 dimer as assayed by both cross-linking and co-immunoprecipitation. The potential function of the different Derlin-1 populations with respect to ER quality control is investigated by analysing their capacity to associate with a misfolded membrane protein fragment. We show for the first time that Derlin-1 can associate with an aberrant membrane protein fragment in the absence of the viral component US11, and conclude that it is the monomeric form of Derlin-1 that interacts with this potential ER-associated degradation substrate. On the basis of these data we propose a model where the pool of active Derlin-1 in the ER membrane can be modulated in response to ER stress.
内质网（ER）是真核生物中蛋白质合成的主要场所。新合成的蛋白质通过质量控制过程进行监测，该过程会将错误折叠或未组装的多肽从内质网中移除，以便蛋白酶体进行降解。这需要错误折叠的蛋白质通过一条途径从内质网腔逆向转运到细胞质中，对于某些底物而言，该途径涉及最近发现的Derlin家族成员。Derlin-1异构体在内质网中以二聚体形式存在，我们现在表明其二聚化受内质网应激调节。通过交联和共免疫沉淀分析，三种不同类型的化学诱导内质网应激显著降低了Derlin-1二聚体的水平。通过分析不同Derlin-1群体与错误折叠的膜蛋白片段结合的能力，研究了它们在内质网质量控制方面的潜在功能。我们首次表明，在没有病毒成分US11的情况下，Derlin-1可以与异常的膜蛋白片段结合，并得出结论，与这种潜在的内质网相关降解底物相互作用的是Derlin-1的单体形式。基于这些数据，我们提出了一个模型，即内质网膜中活性Derlin-1的库可以响应内质网应激而受到调节。
