Active regulator of SIRT1 is required for ribosome biogenesis and function..pdf (2.33 MB)
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Active regulator of SIRT1 is required for ribosome biogenesis and function

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journal contribution
posted on 13.07.2015, 10:31 by John R. P. Knight, Anne E. Willis, J. Milner
Active regulator of SIRT1 (AROS) binds and upregulates SIRT1, an NAD(+)-dependent deacetylase. In addition, AROS binds RPS19, a structural ribosomal protein, which also functions in ribosome biogenesis and is implicated in multiple disease states. The significance of AROS in relation to ribosome biogenesis and function is unknown. Using human cells, we now show that AROS localizes to (i) the nucleolus and (ii) cytoplasmic ribosomes. Co-localization with nucleolar proteins was verified by confocal immunofluorescence of endogenous protein and confirmed by AROS depletion using RNAi. AROS association with cytoplasmic ribosomes was analysed by sucrose density fractionation and immunoprecipitation, revealing that AROS selectively associates with 40S ribosomal subunits and also with polysomes. RNAi-mediated depletion of AROS leads to deficient ribosome biogenesis with aberrant precursor ribosomal RNA processing, reduced 40S subunit ribosomal RNA and 40S ribosomal proteins (including RPS19). Together, this results in a reduction in 40S subunits and translating polysomes, correlating with reduced overall cellular protein synthesis. Interestingly, knockdown of AROS also results in a functionally significant increase in eIF2α phosphorylation. Overall, our results identify AROS as a factor with a role in both ribosome biogenesis and ribosomal function.

History

Citation

Nucleic Acids Research, 2013, 41 (7), pp. 4185-4197

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY

Version

VoR (Version of Record)

Published in

Nucleic Acids Research

Publisher

Oxford University Press

issn

0305-1048

eissn

1362-4962

Acceptance date

10/02/2013

Copyright date

2013

Available date

13/07/2015

Publisher version

http://nar.oxfordjournals.org/content/41/7/4185

Language

en