3月20日,，國際學(xué)術(shù)期刊Cell Research在線發(fā)表了中科院上海生科院生化與細胞所朱學(xué)良組的研究論文“Misfolded Gβ is recruited to cytoplasmic dynein by Nudel for efficient clearance”,。
G蛋白三聚體是G蛋白偶聯(lián)受體（GPCR）信號通路中的重要分子，由a,、b和g三個亞基構(gòu)成,。由于b亞基具有7個重復(fù)的WD結(jié)構(gòu)域形成的螺旋槳狀的空間結(jié)構(gòu)，新合成的Gb需要分子伴侶來對其進行正確的折疊,。而且,，Gb需要與Gg形成異源二聚體才能具有穩(wěn)定的構(gòu)象并形成有功能的蛋白質(zhì)復(fù)合物。對于因為各種原因而錯誤折疊的蛋白質(zhì),，細胞可通過其質(zhì)量控制系統(tǒng)進行清除,，以避免其正常生理功能受到影響。但是,，對于細胞采用怎樣的機制來清除錯誤折疊的Gb,，尤其是其中涉及的時空變化，目前知之甚少,。
朱學(xué)良研究組萬奕含等人研究發(fā)現(xiàn),，錯誤折疊的Gb能夠被泛素化修飾，進而通過泛素-蛋白酶體通路完成降解,。而且,，胞質(zhì)動力蛋白質(zhì)（cytoplasmic dynein）復(fù)合物——一種能在微管上運動的分子馬達（molecular motor）——的調(diào)節(jié)蛋白質(zhì)Nudel 可以直接結(jié)合錯誤折疊的Gb，將其裝載到該分子馬達上,，進而運輸?shù)街行捏w區(qū)域,。這一運輸過程顯著地促進了錯誤折疊的Gb的降解，而在后者過量時則使其積累在中心體周圍形成聚集體（aggresome）,。而且,，Gb的降解不僅有助于對新合成的Gb進行質(zhì)量控制，而且還可能作為Gbg信號的負反饋調(diào)節(jié)機制,。這些發(fā)現(xiàn)提出了Nudel作為動力蛋白調(diào)節(jié)因子的新功能,，并有助于深入理解細胞內(nèi)蛋白質(zhì)量控制系統(tǒng)在空間上的精細調(diào)控。（生物谷 bioon.com）
doi:10.1038/cr.2012.41
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Misfolded Gβ is recruited to cytoplasmic dynein by Nudel for efficient clearance
Yihan Wan, Zhenye Yang, Jing Guo, Qiangge Zhang, Liyong Zeng, Wei Song, Yue Xiao and Xueliang Zhu
The Gβγ heterodimer is an important signal transducer. Gβ, however, is prone to misfolding due to its requirement for Gγ and chaperones for proper folding. How cells dispose of misfolded Gβ (mfGβ) is not clear. Here, we showed that mfGβ was able to be polyubiquitinated and subsequently degraded by the proteasome. It was sequestered in aggresomes after the inhibition of the proteasome activity with MG132. Sustained activation of Gβγ signaling further elevated cellular levels of the ubiquitinated Gβ. Moreover, Nudel, a regulator of cytoplasmic dynein, the microtubule minus end-directed motor, directly interacted with both the unubiquitinated and ubiquitinated mfGβ. Increasing the levels of both mfGβ and Nudel promoted the association of Gβ with both Nudel and dynein, resulting in robust aggresome formation in a dynein-dependent manner. Depletion of Nudel by RNAi reduced the dynein-associated mfGβ, impaired the MG132-induced aggresome formation, and markedly prolonged the half-life of nascent Gβ. Therefore, cytosolic mfGβ is recruited to dynein by Nudel and transported to the centrosome for rapid sequestration and degradation. Such a process not only eliminates mfGβ efficiently for the control of protein quality, but may also help to terminate the Gβγ signaling.
