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Drosophila Mgr, a Prefoldin subunit cooperating with von Hippel Lindau to regulate tubulin stability

Delgehyr, Nathalie and Wieland, Uta and Rangone, Hélène and Pinson, Xavier and Mao, Guojie and Dzhindzhev, Nikola S. and McLean, Doris and Riparbelli, Maria G. and Llamazares, Salud and Callaini, Giuliano and Gonzalez, Cayetano and Glover, David M. (2012) Drosophila Mgr, a Prefoldin subunit cooperating with von Hippel Lindau to regulate tubulin stability. Proceedings of the National Academy of Sciences of the United States of America, 109 (15). pp. 5729-5734. ISSN 0027-8424. PMCID PMC3326472. https://resolver.caltech.edu/CaltechAUTHORS:20200807-170354525

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Abstract

Mutations in Drosophila merry-go-round (mgr) have been known for over two decades to lead to circular mitotic figures and loss of meiotic spindle integrity. However, the identity of its gene product has remained undiscovered. We now show that mgr encodes the Prefoldin subunit counterpart of human von Hippel Lindau binding-protein 1. Depletion of Mgr from cultured cells also leads to formation of monopolar and abnormal spindles and centrosome loss. These phenotypes are associated with reductions of tubulin levels in both mgr flies and mgr RNAi-treated cultured cells. Moreover, mgr spindle defects can be phenocopied by depleting β-tubulin, suggesting Mgr function is required for tubulin stability. Instability of β-tubulin in the mgr larval brain is less pronounced than in either mgr testes or in cultured cells. However, expression of transgenic β-tubulin in the larval brain leads to increased tubulin instability, indicating that Prefoldin might only be required when tubulins are synthesized at high levels. Mgr interacts with Drosophila von Hippel Lindau protein (Vhl). Both proteins interact with unpolymerized tubulins, suggesting they cooperate in regulating tubulin functions. Accordingly, codepletion of Vhl with Mgr gives partial rescue of tubulin instability, monopolar spindle formation, and loss of centrosomes, leading us to propose a requirement for Vhl to promote degradation of incorrectly folded tubulin in the absence of functional Prefoldin. Thus, Vhl may play a pivotal role: promoting microtubule stabilization when tubulins are correctly folded by Prefoldin and tubulin destruction when they are not.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.1108537109DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326472/PubMed CentralArticle
https://doi.org/10.1073/pnas.1617441113DOICorrection
http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1108537109/-/DCSupplementalPublisherSupporting Information
ORCID:
AuthorORCID
Dzhindzhev, Nikola S.0000-0001-9866-3600
Callaini, Giuliano0000-0003-2252-0309
Glover, David M.0000-0003-0956-0103
Additional Information:© 2012 National Academy of Sciences. Edited by Yixian Zheng, Carnegie Institution of Washington, Baltimore, MD, and accepted by the Editorial Board February 23, 2012 (received for review May 31, 2011) We thank Renate Renkawitz-Pohl for anti-β1- and -β2-tubulin antibodies and Matthew Savoian for the β1-tubulin construct; the E7-β-tubulin antibody was developed by Michael Klymkowsky and obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the National Institute of Child Health and Human Development and maintained by the University of Iowa. We thank the Cancer Research Campaign and more recently Cancer Research United Kingdom for supporting this work. N. Delgehyr and U.W. contributed equally to this work. Author contributions: N. Delgehyr, U.W., D.M., C.G., and D.M.G. designed research; N. Delgehyr, U.W., H.R., X.P., G.M., N. Dzhindzhev, D.M., M.R., S.L., and G.C. performed research; N. Delgehyr, U.W., G.M., and N. Dzhindzhev contributed new reagents/analytic tools; N. Delgehyr, U.W., H.R., X.P., D.M., M.R., S.L., G.C., C.G., and D.M.G. analyzed data; and N. Delgehyr, C.G., and D.M.G. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. Y.Z. is a guest editor invited by the Editorial Board. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1108537109/-/DCSupplemental.
Errata:Correction for Delgehyr et al., Drosophila Mgr, a Prefoldin subunit cooperating with von Hippel Lindau to regulate tubulin stability Proceedings of the National Academy of Sciences Nov 2016, 113 (48) E7867-E7868; DOI: 10.1073/pnas.1617441113
Funders:
Funding AgencyGrant Number
Cancer Research CampaignUNSPECIFIED
Cancer Research UKUNSPECIFIED
Subject Keywords:folding | chaperone | Gim | E3 ubiquitin ligase
Issue or Number:15
PubMed Central ID:PMC3326472
Record Number:CaltechAUTHORS:20200807-170354525
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200807-170354525
Official Citation:Drosophila Prefoldin, Vhl, and tubulin stability Nathalie Delgehyr, Uta Wieland, Hélène Rangone, Xavier Pinson, Guojie Mao, Nikola S. Dzhindzhev, Doris McLean, Maria G. Riparbelli, Salud Llamazares, Giuliano Callaini, Cayetano Gonzalez, David M. Glover Proceedings of the National Academy of Sciences Apr 2012, 109 (15) 5729-5734; DOI: 10.1073/pnas.1108537109
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104873
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:11 Aug 2020 14:16
Last Modified:11 Aug 2020 14:16

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