SIRT2 Isoforms in Neurodegenerative Diseases & Cancer

Silent information regulator type 2 (Sirtuin 2 or SIRT2) is a highly evolutionarily conserved NAD+ dependent deacetylase. SIRT2 is the only Sirtuin that acts in the cytosol. It expresses in almost all tissues, but most abundantly in the central nervous system. While SIRT2 is classified as a type III histone deacetylase, it is also capable of performing this function on non-histone acetyllysine-bearing substrates. In addition, SIRT2 is capable of ADP-ribosylation, demyristoylase activity, and long-chain fatty acid deacylation.¹

Structure & Function

The structure of SIRT2 consists of an N-terminal nuclear export sequence, a catalytic core, and a C-terminal nuclear import sequence. The catalytic core comprises a larger NAD+ binding Rossman fold domain hinged to a smaller zinc-binding domain. Together, these features create a large groove capable of interacting with NAD+ (Rossman domain) and negotiating protein-protein interactions between SIRT2 and its substrates (zinc-binding domain).²

Given its intracellular mobility, catalytic properties, and protein interactivity, SIRT2 has been found to participate in diverse cellular functions: DNA replication, transcription, & translation; epigenetic & post-translational modifications; genome integrity; autophagy; mitosis; lipid metabolism signaling; glucose metabolism signaling; inflammation; oxidative stress; cardiac & hepatic protection; and, most controversially, neurodegenerative diseases & cancer.³

Over the years, conflicting evidence both implicates and exonerates SIRT2 in neurological disorders and cancer. There are arguments for protective, coincidental, and causative aspects of SIRT2 in these disorders.⁴ Why should this be, and what could possibly disentangle these conflicting lines of evidence?

Isoforms of SIRT2

Currently, scientists identify 3 distinct SIRT2 isoforms. Isoforms 1 and 2 are fully functional deacetylases that can shuttle between the cytoplasm and the nucleus. Isoform 1, at 43 kDa, is expressed from all 16 exons of the SIRT2 gene and is predominantly found in skeletal muscle cytoplasm. Isoform 2, at 39 kDa, lacks expressed sequences from exons 1 through 3, predominantly exists in the fully mature central nervous system, and distributes across both the nucleus and cytoplasm. The missing first 37 amino acids of the full-length SIRT2 impair its ability to associate with chromatin.

Isoform 5 (murine isoform 3), at 36kDa, skips exons 2 through 4 and increasingly accumulates in aging central nervous tissue. Due to the omission of N-terminal amino acids 6 through 76, this splice variant lacks a functional nuclear export sequence (amino acids 41-51) and canonical catalytic capabilities, remaining confined to the nucleus.⁵ Isoform 5 does seem to confer epigenetic resistance to HBV infection.⁶

Looking Ahead

Could the key to resolving the conflicting roles of SIRT2 in disease depend upon which isoform is predominantly involved in a given disease state? Is it possible to reverse these diseases by silencing the prevailing isoform and inducing one that appropriately expresses in healthy tissue? Given the differing localizing and functional properties of the known isoforms, the particular SIRT2 splice variant present may be more important than the total amount of SIRT2 in a given tissue.

References

1. Liu, Y. et al. (2020) Emerging Role of Sirtuin 2 in Parkinson’s Disease. Front. Aging Neurosci., 11:372, 1-11. Review. https://doi.org/10.3389/fnagi.2019.00372
2. Zhang, F. and Li, B. (2022) Will Sirtuin 2 Be a Promising Target for Neuroinflammatory disorders? Front. Cell Neurosci., 16:915587, 1-13. Review. https://doi.org/10.3389/fncel.2022.915587
3. Zhu, C. et al (2022) Multiple Roles of SIRT2 in Regulating Physiological and Pathological Signal Transduction. Hindawi Genetics Research, 2022:9282484, 1-14. Review. https://doi.org/10.1155/2022/9282484
4. Wang, Y. et al. (2019) SIRT2: Controversy and multiple roles in disease and physiology. Ageing Research Review, 55(6):100961. Review. https://doi.org/10.1016/j.arr.2019.100961
5. Eldridge, M. J. G. et al (2020) Active nuclear import of the deacetylase Sirtuin-2 is controlled by its C-terminus and importins. Nature Scientific Reports, 10:2034, 1-12. https://doi.org/10.1038/s41598-020-58397-6
6. Piracha, Z. Z. et al (2020) An Alternatively Spliced Sirtuin 2 Isoform 5 Inhibits Hepatitis B Virus Replication from cccDNA by Repressing Epigenetic Modifications Made by Histone Lysine Methyltransferases. Journal of Virology, 94(16)  https://doi.org/10.1128/JVI.00926-20