The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and proteostasis

Kirsten Kuhlbrodt, Philipp Christoph Janiesch, E. Kévei, Alexandra Segref, Roja Barikbin, Thorsten Hoppe

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Protein ubiquitylation is a key post-translational control mechanism contributing to different physiological processes, such as signal transduction and ageing. The size and linkage of a ubiquitin chain, which determines whether a substrate is efficiently targeted for proteasomal degradation, is determined by the interplay between ubiquitylation and deubiquitylation. A conserved factor that orchestrates distinct substrate-processing co-regulators in diverse species is the ubiquitin-selective chaperone CDC-48 (also known as p97). Several deubiquitylation enzymes (DUBs) have been shown to interact with CDC-48/p97, but the mechanistic and physiological relevance of these interactions remained elusive. Here we report a synergistic cooperation between CDC-48 and ATX-3 (the Caenorhabditis elegans orthologue of ataxin-3) in ubiquitin-mediated proteolysis and ageing regulation. Surprisingly, worms deficient for both cdc-48.1 and atx-3 demonstrated extended lifespan by up to 50%, mediated through the insulin-insulin-like growth factor 1 (IGF-1) signalling pathway. As lifespan extension specifically depends on the deubiquitylation activity of ATX-3, our findings identify a mechanistic link between protein degradation and longevity through editing of the ubiquitylation status of substrates involved in insulin-IGF-1 signalling.

Original languageEnglish
Pages (from-to)273-281
Number of pages9
JournalNature Cell Biology
Volume13
Issue number3
DOIs
Publication statusPublished - Mar 2011

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Machado-Joseph Disease
Ubiquitination
Centers for Disease Control and Prevention (U.S.)
Ubiquitin
Somatomedins
Proteolysis
Insulin
Physiological Phenomena
Caenorhabditis elegans
Signal Transduction
Enzymes
Proteins

ASJC Scopus subject areas

  • Cell Biology

Cite this

Kuhlbrodt, K., Janiesch, P. C., Kévei, E., Segref, A., Barikbin, R., & Hoppe, T. (2011). The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and proteostasis. Nature Cell Biology, 13(3), 273-281. https://doi.org/10.1038/ncb2200

The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and proteostasis. / Kuhlbrodt, Kirsten; Janiesch, Philipp Christoph; Kévei, E.; Segref, Alexandra; Barikbin, Roja; Hoppe, Thorsten.

In: Nature Cell Biology, Vol. 13, No. 3, 03.2011, p. 273-281.

Research output: Contribution to journalArticle

Kuhlbrodt, K, Janiesch, PC, Kévei, E, Segref, A, Barikbin, R & Hoppe, T 2011, 'The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and proteostasis', Nature Cell Biology, vol. 13, no. 3, pp. 273-281. https://doi.org/10.1038/ncb2200
Kuhlbrodt, Kirsten ; Janiesch, Philipp Christoph ; Kévei, E. ; Segref, Alexandra ; Barikbin, Roja ; Hoppe, Thorsten. / The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and proteostasis. In: Nature Cell Biology. 2011 ; Vol. 13, No. 3. pp. 273-281.
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