內(nèi)質(zhì)網(wǎng)內(nèi)合成的蛋白質(zhì)質(zhì)量會(huì)受到嚴(yán)格控制,，未折疊或折疊錯(cuò)誤的蛋白質(zhì)會(huì)通過(guò)內(nèi)質(zhì)網(wǎng)介導(dǎo)的途徑降解,。折疊錯(cuò)誤的蛋白質(zhì)被識(shí)別并轉(zhuǎn)運(yùn)至細(xì)胞質(zhì)中,，在細(xì)胞質(zhì)中泛素化后由26S蛋白酶體降解,。發(fā)表在11月30日的《分子細(xì)胞》（Molecular Cell）上的一項(xiàng)最新研究,，揭示了哺乳動(dòng)物細(xì)胞內(nèi)非糖基化蛋白質(zhì)的降解途徑,，該途徑與以前發(fā)現(xiàn)的糖基化蛋白的降解途徑有所不同。
免疫球蛋白κ輕鏈（IgκLC）是分子伴侶BiP的非糖基化底物,，在它與重鏈結(jié)合之前不分泌,，會(huì)被降解。美國(guó)圣猶大兒童研究醫(yī)院的研究人員對(duì)老鼠漿細(xì)胞瘤中IgκLC的降解進(jìn)行實(shí)驗(yàn)研究,，發(fā)現(xiàn)其降解由內(nèi)質(zhì)網(wǎng)介導(dǎo),，需要經(jīng)過(guò)泛素化,。它以部分氧化（ox1）和完全氧化（ox2）兩種形式存在,，ox2被還原為ox1才能泛素化，也只有ox1能夠與Herp和Derlin1相互作用。通過(guò)用免疫共沉淀和免疫印跡等方法對(duì)不同細(xì)胞系的裂解產(chǎn)物進(jìn)行分析,，研究人員發(fā)現(xiàn),，Herp與Derlin1、p97和泛素連接酶Hrd1組成復(fù)合體參與非糖基化的IgκLC的降解,，同時(shí)Herp與泛素化蛋白和26S蛋白酶體之間也存在相互作用,，可能在底物和蛋白酶體的連接中起作用。
Herp也能夠結(jié)合其它兩種BiP的非糖基化底物,，但是不能結(jié)合鈣聯(lián)蛋白的糖基化底物,。Herp表達(dá)水平的降低能夠抑制BiP底物的降解，而不影響鈣聯(lián)蛋白的底物的降解,。這表明不同類型底物的內(nèi)質(zhì)網(wǎng)介導(dǎo)降解途徑有所不同,，可能和底物的糖基化程度或者分子伴侶的類型有關(guān)。但是需要對(duì)更多底物進(jìn)行研究來(lái)檢驗(yàn)這一推論,。（穆宏平/編譯）
原始出處:
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
[email protected]
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.
