SIRT2 as a Therapeutic Target for Age-Related Disorders

Abstract

Sirtuin proteins are conserved regulators of aging that have recently emerged as important modifiers of several diseases which commonly occur later in life such as cancer, diabetes, cardiovascular, and neurodegenerative diseases. In mammals, there are seven sirtuins (SIRT1-7), which display diversity in subcellular localization and function. SIRT1 has received much of attention due to its possible impact on longevity, while important biological and therapeutic roles of other sirtuins have been underestimated and just recently recognized. Here we focus on SIRT2, a member of the sirtuin family, and discuss its role in cellular and tissue-specific functions. This review summarizes the main scientific advances on SIRT2 protein biology and explores its potential as a therapeutic target for treatment of age-related disorders.

Keywords: SIRT2; aging; cancer; metabolic syndrome; neurodegenerative disorder.

Figure 1

Cellular distribution of mammalian sirtuins. Mammals possess seven sirtuins, SIRT1–7, that have a NAD⁺-dependent catalytic core domain in common. Additional variable N-terminal and C-terminal sequences flank this core domain leading to diverse subcellular localizations that may account for differences in their biological functions as well as different substrates and binding partners within the cell. SIRT1 is mainly nuclear, modulating, amongst others, chromatin structure by deacetylating specific lysine residues in histones H1, H3, and H4, although it can transiently be found in the cytoplasm. SIRT2, the closest homolog of SIRT1, is primarily a cytoplasmic protein, but can transiently shuttle into the nucleus during mitosis, where it deacetylates Lys-56 of histone H3 and Lys-16 of histone H4. In the cytoplasm, SIRT2 deacetylates microtubules, in particular α-tubulin at Lys-40 and a variety of other substrates (Table 1). SIRT3, SIRT4, and SIRT5 were found to co-localize with mitochondria indicating key regulative roles in metabolism and energy usage of the cell. SIRT6 is a nuclear protein found to regulate DNA repair, while SIRT7 co-localizes with the nucleolus and was shown to be involved in rRNA transcription.