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

Cell Reports

Ullas Kolthur-Seetharam¹  Deepti Ramachandran¹  Shaunak Deota¹  Tandrika Chattopadhyay¹  Babukrishna Maniyadath¹  Anne Gonzalez-de-Peredo²  Amit Fulzele²  Beatriz Camacho³  Eric Armstrong³  John M. Denu³ 

[1] Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India;Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS - UMR 5089, Toulouse 31077, France;Wisconsin Institute for Discovery and Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, UW-Madison, Madison, WI 53715, USA;

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

DOI  :  10.1016/j.celrep.2017.03.012

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown