Molecular Cell：非糖基化蛋白的内质网介导降解途径

生物谷

    内质网内合成的蛋白质质量会受到严格控制，未折叠或折叠错误的蛋白质会通过内质网介导的途径降解。折叠错误的蛋白质被识别并转运至细胞质中，在细胞质中泛素化后由26S蛋白酶体降解。发表在11月30日的《分子细胞》（Molecular Cell）上的一项最新研究，揭示了哺乳动物细胞内非糖基化蛋白质的降解途径，该途径与以前发现的糖基化蛋白的降解途径有所不同。

    免疫球蛋白κ轻链（IgκLC）是分子伴侣BiP的非糖基化底物，在它与重链结合之前不分泌，会被降解。美国圣犹大儿童研究医院的研究人员对老鼠浆细胞瘤中IgκLC的降解进行实验研究，发现其降解由内质网介导，需要经过泛素化。它以部分氧化（ox1）和完全氧化（ox2）两种形式存在，ox2被还原为ox1才能泛素化，也只有ox1能够与Herp和Derlin1相互作用。通过用免疫共沉淀和免疫印迹等方法对不同细胞系的裂解产物进行分析，研究人员发现，Herp与Derlin1、p97和泛素连接酶Hrd1组成复合体参与非糖基化的IgκLC的降解，同时Herp与泛素化蛋白和26S蛋白酶体之间也存在相互作用，可能在底物和蛋白酶体的连接中起作用。

    Herp也能够结合其它两种BiP的非糖基化底物，但是不能结合钙联蛋白的糖基化底物。Herp表达水平的降低能够抑制BiP底物的降解，而不影响钙联蛋白的底物的降解。这表明不同类型底物的内质网介导降解途径有所不同，可能和底物的糖基化程度或者分子伴侣的类型有关。但是需要对更多底物进行研究来检验这一推论。（穆宏平/编译）

原始出处:

Molecular Cell, Vol 28, 544-554, 30 November 2007

Article

Characterization of an ERAD Pathway for Nonglycosylated BiP Substrates, which Require Herp

Yuki Okuda-Shimizu1 and Linda M. Hendershot1,

1 Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA

Corresponding author
Linda M. Hendershot
linda.hendershot@stjude.org

To investigate the disposal of nonglycosylated BiP substrates, we used a nonsecreted κ LC, which exists in partially (ox1) and completely (ox2) oxidized states. The ox2 form is partially reduced in order to be degraded, and only the ox1 form is ubiquitinated and associates with both Herp and Derlin-1. Herp is in a complex with ubiquitinated proteins and with the 26S proteasome, suggesting that it plays a role in linking substrates with the proteasome. Overexpressed Herp also interacts with two other BiP substrates, but not with two calnexin substrates. Either expression of p97 or Hrd1 mutants, which are in a complex with Herp and Derlin-1, or reduction of Herp levels inhibited the degradation of the BiP substrates, whereas the latter had no effect on the degradation of the calnexin substrates. This result suggests that there is some distinction in the pathways used to dispose of these two types of ERAD substrates.