3月20日，国际学术期刊Cell Research在线发表了中科院上海生科院生化与细胞所朱学良组的研究论文“Misfolded Gβ is recruited to cytoplasmic dynein by Nudel for efficient clearance”。
G蛋白三聚体是G蛋白偶联受体（GPCR）信号通路中的重要分子，由a、b和g三个亚基构成。由于b亚基具有7个重复的WD结构域形成的螺旋桨状的空间结构，新合成的Gb需要分子伴侣来对其进行正确的折叠。而且，Gb需要与Gg形成异源二聚体才能具有稳定的构象并形成有功能的蛋白质复合物。对于因为各种原因而错误折叠的蛋白质，细胞可通过其质量控制系统进行清除，以避免其正常生理功能受到影响。但是，对于细胞采用怎样的机制来清除错误折叠的Gb，尤其是其中涉及的时空变化，目前知之甚少。
朱学良研究组万奕含等人研究发现，错误折叠的Gb能够被泛素化修饰，进而通过泛素-蛋白酶体通路完成降解。而且，胞质动力蛋白质（cytoplasmic dynein）复合物——一种能在微管上运动的分子马达（molecular motor）——的调节蛋白质Nudel 可以直接结合错误折叠的Gb，将其装载到该分子马达上，进而运输到中心体区域。这一运输过程显著地促进了错误折叠的Gb的降解，而在后者过量时则使其积累在中心体周围形成聚集体（aggresome）。而且，Gb的降解不仅有助于对新合成的Gb进行质量控制，而且还可能作为Gbg信号的负反馈调节机制。这些发现提出了Nudel作为动力蛋白调节因子的新功能，并有助于深入理解细胞内蛋白质量控制系统在空间上的精细调控。（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.
