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

Publication date: 28 March 2017
Source:Cell Reports, Volume 18, Issue 13
Author(s): Shaunak Deota, Tandrika Chattopadhyay, Deepti Ramachandran, Eric Armstrong, Beatriz Camacho, Babukrishna Maniyadath, Amit Fulzele, Anne Gonzalez-de-Peredo, John M. Denu, Ullas Kolthur-Seetharam
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.

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Teaser

Deota et al. identify SIRT1-ΔE2, a tissue-restricted SIRT1 isoform, and a conserved domain within SIRT1 that results in specific interactions. This domain is linked to metabolic homeostasis and DNA damage response and may point to strategies for precise modulation of SIRT1.


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