Identification of a Tissue-Restricted Isoform of SIRT1 Defines a Regulatory Domain that Encodes Specificity
Shaunak Deota,
Tandrika Chattopadhyay,
Deepti Ramachandran,
Eric Armstrong,
Beatriz Camacho,
Babukrishna Maniyadath,
Amit Fulzele,
Anne Gonzalez-de-Peredo,
John M. Denu,
Ullas Kolthur-Seetharam
Affiliations
Shaunak Deota
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India
Tandrika Chattopadhyay
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India
Deepti Ramachandran
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India
Eric Armstrong
Wisconsin Institute for Discovery and Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, UW-Madison, Madison, WI 53715, USA
Beatriz Camacho
Wisconsin Institute for Discovery and Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, UW-Madison, Madison, WI 53715, USA
Babukrishna Maniyadath
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India
Amit Fulzele
Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS - UMR 5089, Toulouse 31077, France
Anne Gonzalez-de-Peredo
Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS - UMR 5089, Toulouse 31077, France
John M. Denu
Wisconsin Institute for Discovery and Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, UW-Madison, Madison, WI 53715, USA
Ullas Kolthur-Seetharam
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India
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.
