VBP1 facilitates proteasome and autophagy-mediated degradation of MutS homologue hMSH4

Yang Xu; Chengtao Her

doi:10.1096/fj.13-235127

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VBP1 facilitates proteasome and autophagy-mediated degradation of MutS homologue hMSH4

Journal article

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VBP1 facilitates proteasome and autophagy-mediated degradation of MutS homologue hMSH4

Yang Xu and Chengtao Her

The FASEB journal, Vol.27(12), pp.4799-4810

12/2013

DOI: https://doi.org/10.1096/fj.13-235127

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https://hdl.handle.net/2376/107129

PMCID: PMC3834780

PMID: 23964080

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Abstract

Humans

Cell Cycle Proteins - metabolism

Adenosine Triphosphatases - metabolism

Homeostasis

Nuclear Proteins - metabolism

Autophagy

Ubiquitination

Carrier Proteins - metabolism

Proteolysis

HEK293 Cells

Cell Line, Tumor

Protein Binding

Proteasome Endopeptidase Complex - metabolism

Ubiquitination is an important mechanism for the regulation of diverse cellular functions, including proteolysis and DNA repair. The human MutS family protein hMSH4 functions in meiotic recombinational DNA double-strand break (DSB) repair. It was previously observed that hMSH4 interacts with the von Hippel-Lindau binding protein 1 (VBP1), a partner of the VHL ubiquitin E3 ligase as well as a subunit of the prefoldin complex. In this study we address how ubiquitination regulates the homeostasis of hMSH4 in the human embryonic kidney cell line HEK293T. We demonstrate that VBP1 targets hMSH4 for degradation and identify a new VBP1 binding partner, p97, an AAA(+) ATPase involved in protein degradation and DNA damage response. VBP1, VHL, and p97 coexist in the hMSH4 immunocomplex and regulate the polyubiquitination of hMSH4. Furthermore, the results of this study demonstrate that VBP1 acts together with p97 to regulate hMSH4 degradation. Overall, this study has revealed a molecular mechanism by which VBP1 controls the levels of hMSH4 by ubiquitination in mitotic cells. Such a mechanism may be important for controlling the role of hMSH4 in regulating homologous recombination and nonhomologous DNA end joining-mediated DSB repair in human cells.

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Title: VBP1 facilitates proteasome and autophagy-mediated degradation of MutS homologue hMSH4
Creators: Yang Xu - 1School of Molecular Biosciences, Mail Drop 64-7520, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-7520, USA. cher@wsu.edu
Chengtao Her
Publication Details: The FASEB journal, Vol.27(12), pp.4799-4810
Academic Unit: Molecular Biosciences, School of
Publisher: United States
Grant note: R01 GM084353 / NIGMS NIH HHS GM084353 / NIGMS NIH HHS
Identifiers: 99900546997301842
Language: English
Resource Type: Journal article