title: Misfolded Gβ is recruited to cytoplasmic dynein by Nudel for efficient clearance.
abstract: 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.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
authors.forename: Yihan
authors.initials: Y
authors.lastname: Wan
authors.forename: Zhenye
authors.initials: Z
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.forename: Qiangge
authors.initials: Q
authors.lastname: Zhang
authors.forename: Liyong
authors.initials: L
authors.lastname: Zeng
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiao
authors.forename: Xueliang
authors.initials: X
authors.lastname: Zhu
mesh_terms: D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D018385:Centrosome / Q000378:metabolism; D002522:Chlorocebus aethiops; D056445:Cytoplasmic Dyneins / Q000235:genetics / Q000378:metabolism*; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007976:Leupeptins / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D011485:Protein Binding / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D044387:GTP-Binding Protein beta Subunits; D007976:Leupeptins; C421108:NDEL1 protein, human; D056445:Cytoplasmic Dyneins; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde