Protein targeting and degradation are coupled for elimination of mislocalized proteins.
Protein targeting and degradation are coupled for elimination of mislocalized proteins.
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DOI：
10.1038/nature10181
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发表时间：
2011-07-10
期刊：
影响因子：
64.8
通讯作者：
Hegde, Ramanujan S.
中科院分区：
文献类型：
--
作者：
Hessa, Tara;Sharma, Ajay;Mariappan, Malaiyalam;Eshleman, Heather D.;Gutierrez, Erik;Hegde, Ramanujan S.
很大一部分基因组编码膜蛋白，通过专门的靶向途径将膜蛋白输送到内质网。靶向失败的膜蛋白必须迅速降解，以避免聚集和破坏胞质蛋白的稳态。错位蛋白(MLP)的降解机制尚不清楚。在这里，我们重建了MLP的体外降解，以确定参与这一途径的因素。我们发现，与核糖体捆绑在一起的新生膜蛋白不是泛素化的底物，除非它们被释放到细胞质中。它们的不适当释放导致被Bag6复合体捕获，Bag6复合体是最近发现的一种核糖体结合伴侣。Bag6复合体的捕获依赖于未加工或未插入的疏水结构域，这些结构域将MLP与潜在的胞浆蛋白区分开来。这些Bag6客户的子集被转移到TRC40用于膜插入，而其余的被迅速泛化。Bag6复合体的耗尽会选择性地损害MLP的有效泛素化。因此，通过存在于合成新生细胞膜蛋白的核糖体上，Bag6复合体将靶向和泛素化途径联系起来。我们认为，这种耦合允许快速追踪MLP的降解，而不会徒劳地接触细胞质折叠机械。
A substantial proportion of the genome encodes membrane proteins that are delivered to the endoplasmic reticulum by dedicated targeting pathways. Membrane proteins that fail targeting must be rapidly degraded to avoid aggregation and disruption of cytosolic protein homeostasis. The mechanisms of mislocalized protein (MLP) degradation are unknown. Here, we reconstitute MLP degradation in vitro to identify factors involved in this pathway. We find that nascent membrane proteins tethered to ribosomes are not substrates for ubiquitination unless they are released into the cytosol. Their inappropriate release results in capture by the Bag6 complex, a recently identified ribosome-associating chaperone. Bag6 complex capture depends on unprocessed or non-inserted hydrophobic domains that distinguish MLPs from potential cytosolic proteins. A subset of these Bag6 clients is transferred to TRC40 for membrane insertion, while the remainder are rapidly ubiquitinated. Depletion of the Bag6 complex impairs efficient ubiquitination selectively of MLPs. Thus, by its presence on ribosomes synthesizing nascent membrane proteins, the Bag6 complex links targeting and ubiquitination pathways. We propose that such coupling permits fast-tracking of MLPs for degradation without futile engagement of cytosolic folding machinery.
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影响因子：
56.9
作者：
Cole, NB;Smith, CL;LippincottSchwartz, J
通讯作者：
LippincottSchwartz, J
影响因子：
3.3
作者：
Emerman AB;Zhang ZR;Chakrabarti O;Hegde RS
通讯作者：
Hegde RS
影响因子：
4
作者：
Leznicki, Pawel;Clancy, Anne;High, Stephen
通讯作者：
High, Stephen
影响因子：
4.4
作者：
Lehner, B;Semple, JI;Sanderson, CM
通讯作者：
Sanderson, CM
DOI：
10.1073/pnas.83.22.8604
发表时间：
1986-11-01
影响因子：
11.1
作者：
KRIEG, UC;WALTER, P;JOHNSON, AE
通讯作者：
JOHNSON, AE