Efficient chaperone-mediated tubulin biogenesis is essential for cell division and cell migration in C. elegans

Lundin, Victor; Srayko, Martin; Hyman, Anthony A.; Leroux, Michel R.

doi:10.1016/j.ydbio.2007.10.022

Cited by 79 publications

(76 citation statements)

References 78 publications

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“…Loss of prefoldin in Caenorhabditis elegans is lethal because of a high demand for tubulin in mitotic cells in the embryo (24). In plants, prefoldin 6 has been shown to be required for normal MT dynamics and organization (25).…”

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confidence: 99%

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

Delgehyr

Wieland

Rangone

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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.

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confidence: 99%

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

Delgehyr

Wieland

Rangone

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…This interaction of a chaperone with a cytoskeletal element is not unique to this class of chaperones. Additional chaperones interact with motor proteins and cytoskeletal elements; these include the sHsps, which interact with actin filaments and tubulin (Gusev et al 2002;Mitra et al 2007), the UNC-45/Cro1/She4p (UCS) family of chaperones that interact with myosin (Hutagalung et al 2002), and a plethora of tubulin chaperones, which include cofactors and chaperonins (Lewis et al 1997;Lundin et al 2008).…”

Section: Discussionmentioning

confidence: 99%

The microtubule-associated protein, NUD-1, exhibits chaperone activity in vitro

Faircloth

Churchill

Caldwell

2009

Cell Stress and Chaperones

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Regulation of cell division requires the concerted function of proteins and protein complexes that properly mediate cytoskeletal dynamics. NudC is an evolutionarily conserved protein of undetermined function that associates with microtubules and interacts with several key regulators of mitosis, such as polo-kinase 1 (Plk1) and dynein. NudC is essential for proper mitotic progression, and homologs have been identified in species ranging from fungi to humans. In this paper, we report the characterization of the Caenorhabditis elegans NudC homolog, NUD-1, as a protein exhibiting molecular chaperone activity. All NudC/NUD-1 proteins share a conserved p23/HSP20 domain predicted by three-dimensional modeling [GarciaRanea, Mirey, Camonis, Valencia, FEBS Lett 529(2-3): [162][163][164][165][166][167] 2002]. We demonstrate that nematode NUD-1 is able to prevent the aggregation of two substrate proteins, citrate synthase (CS) and luciferase, at stoichiometric concentrations. Further, NUD-1 also protects the native state of CS from thermal inactivation by significantly reducing the inactivation rate of this enzyme. To further determine if NUD-1/substrate complexes were productive or simply "dead-end" unfolding intermediates, a luciferase refolding assay was utilized. Following thermal denaturation, rabbit reticulocyte lysate and ATP were added and luciferase activity measured. In the presence of NUD-1, nearly all of the luciferase activity was regained, indicating that unfolded intermediates complexed with NUD-1 could be refolded. These studies represent the first functional evidence for a member of this mitotically essential protein family as having chaperone activity and facilitates elucidation of the role such proteins play in chaperone complexes utilized in cell division. C. elegans NUD-1 is a member of an evolutionary conserved protein family of unknown function involved in the regulation of cytoskeletal dynamics. NUD-1 and its mammalian homolog, NudC, function with the dynein motor complex to ensure proper cell division, and knockdown or overexpression of these proteins leads to disruption of mitosis. In this paper, we show that NUD-1 possesses ATP-independent chaperone activity comparable to that of small heat shock proteins and cochaperones and that changes in phosphorylation state functionally alter chaperone activity in a phosphomimetic NUD-1 mutant.

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“…Similarly, deletion of single or multiple subunits of prefoldin in yeast results in increased sensitivity to microtubule destabilizing agents and to low temperature stress, and retarded growth with disruption in actin/tubulin-based cytoskeletal structures (1,3,6,9,10). In Caenorhabditis elegans, reduction of functional prefoldin subunits 1, 2, 3, and 6 by RNAi result in developmental defects such as improper cell division that can lead to embryonic lethality (11)(12)(13). In Arabidopsis, prefoldin 6 is necessary for proper microtubule organization and dynamics (14,15).…”

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confidence: 99%

Prefoldin 5 Is Required for Normal Sensory and Neuronal Development in a Murine Model

Lee

Smith

Jordan

et al. 2011

Journal of Biological Chemistry

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Molecular chaperones and co-chaperones are crucial for cellular development and maintenance as they assist in protein folding and stabilization of unfolded or misfolded proteins. Prefoldin (PFDN), a ubiquitously expressed heterohexameric co-chaperone, is necessary for proper folding of nascent proteins, in particular, tubulin and actin. Here we show that a genetic disruption in the murine Pfdn5 gene, a subunit of prefoldin, causes a syndrome characterized by photoreceptor degeneration, central nervous system abnormalities, and male infertility. Our data indicate that a missense mutation in Pfdn5, may cause these phenotypes through a reduction in formation of microtubules and microfilaments, which are necessary for the development of cilia and cytoskeletal structures, respectively. The diversity of phenotypes demonstrated by models carrying mutations in different PFDN subunits suggests that each PFDN subunit must confer a distinct substrate specificity to the prefoldin holocomplex.

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Efficient chaperone-mediated tubulin biogenesis is essential for cell division and cell migration in C. elegans

Cited by 79 publications

References 78 publications

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

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

The microtubule-associated protein, NUD-1, exhibits chaperone activity in vitro

Prefoldin 5 Is Required for Normal Sensory and Neuronal Development in a Murine Model

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