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Cell Rep. 2017 Mar 28;18(13):3069-3077. doi: 10.1016/j.celrep.2017.03.012.

Identification of a Tissue-Restricted Isoform of SIRT1 Defines a Regulatory Domain that Encodes Specificity.

Author information

1
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
2
Wisconsin Institute for Discovery and Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, UW-Madison, Madison, WI 53715, USA.
3
Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS - UMR 5089, Toulouse 31077, France.
4
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India. Electronic address: ullas@tifr.res.in.

Abstract

The conserved NAD+-dependent deacylase SIRT1 plays pivotal, sometimes contrasting, roles in diverse physiological and pathophysiological conditions. In this study, we uncover a tissue-restricted isoform of SIRT1 (SIRT1-ΔE2) that lacks exon 2 (E2). Candidate-based screening of SIRT1 substrates demonstrated that the domain encoded by this exon plays a key role in specifying SIRT1 protein-protein interactions. The E2 domain of SIRT1 was both necessary and sufficient for PGC1α binding, enhanced interaction with p53, and thus downstream functions. Since SIRT1-FL and SIRT1-ΔE2 were found to have similar intrinsic catalytic activities, we propose that the E2 domain tethers specific substrate proteins. Given the absence of SIRT1-ΔE2 in liver, our findings provide insight into the role of the E2 domain in specifying "metabolic functions" of SIRT1-FL. Identification of SIRT1-ΔE2 and the conserved specificity domain will enhance our understanding of SIRT1 and guide the development of therapeutic interventions.

KEYWORDS:

AKT; DNA damage; E2; PGC1α; PPARα; SIRT1; SIRT1-Δ; insulin signaling; isoform; p53; specificity domain; β-oxidation

PMID:
28355560
PMCID:
PMC5545126
DOI:
10.1016/j.celrep.2017.03.012
[Indexed for MEDLINE]
Free PMC Article

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