title: The L279P mutation of nuclear distribution gene C (NudC) influences its chaperone activity and lissencephaly protein 1 (LIS1) stability.
abstract: LIS1, a gene mutated in classical lissencephaly, plays essential roles in cytoplasmic dynein regulation, mitosis and cell migration. However, the regulation of LIS1 (lissencephaly protein 1) protein remains largely unknown. Genetic studies in Aspergillus nidulans have uncovered that the Nud (nuclear distribution) pathway is involved in the regulation of cytoplasmic dynein complex and a temperature-sensitive mutation in the nudC gene (L146P) greatly reduces the protein levels of NudF, an Aspergillus ortholog of LIS1. Here, we showed that L146 in Aspergillus NudC and its flanking region were highly conservative during evolution. The similar mutation in human NudC (L279P) obviously led to reduced LIS1 and cellular phenotypes similar to those of LIS1 down-regulation. To explore the underlying mechanism, we found that the p23 domain-containing protein NudC bound to the molecular chaperone Hsp90, which is also associated with LIS1. Inhibition of Hsp90 chaperone function by either geldanamycin or radicicol resulted in a decrease in LIS1 levels. Ectopic expression of Hsp90 partially reversed the degradation of LIS1 caused by overexpression of NudC-L279P. Furthermore, NudC was found to regulate the ATPase activity of Hsp90, which was repressed by the mutation of L279P. Interestingly, NudC itself was shown to possess a chaperone function, which also was suppressed by the L279P mutation. Together, these data suggest that NudC may be involved in the regulation of LIS1 stability by its chaperone function.
authors.affiliation: Department of Cell Biology and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Zhu
authors.forename: Xunyan
authors.initials: X
authors.lastname: Liu
authors.forename: Qi
authors.initials: Q
authors.lastname: Jin
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Cai
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Yang
authors.forename: Tianhua
authors.initials: T
authors.lastname: Zhou
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D001233:Aspergillus nidulans / Q000235:genetics / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004795:Enzyme Stability / Q000187:drug effects / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins; D006367:HeLa Cells; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015027:Zebrafish
chemical_list: D016227:Benzoquinones; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018942:Macrolides; D008869:Microtubule-Associated Proteins; C512648:NUDC protein, human; D009687:Nuclear Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; C035359:monorden; C001277:geldanamycin