Distinct regulation of mitochondrial localization and stability of two human Sirt5 isoforms: Regulation of two human SIRT5 isoforms
Open accessAbstract
Seven human Sir2 homologues (sirtuin) have been identified to date. In this study, we clarified the mechanism of subcellular localization of two SIRT5 isoforms (i.e., SIRT5(iso1) and SIRT5(iso2) ) encoded by the human SIRT5 gene and whose C-termini slightly differ from each other. Although both isoforms contain cleavable mitochondrial targeting signals at their N-termini, we found that the cleaved SIRT5(iso2) was localized mainly in mitochondria, whereas the cleaved SIRT5(iso1) was localized in both mitochondria and cytoplasm. SIRT5ΔC, which is composed of only the common domain, showed the same mitochondrial localization as that of SIRT5(iso2) . These results suggest that the cytoplasmic localization of cleaved SIRT5(iso1) is dependent on the SIRT5(iso1) -specific C-terminus. Further analysis showed that the C-terminus of SIRT5(iso2) , which is rich in hydrophobic amino acid residues, functions as a mitochondrial membrane insertion signal. In addition, a de novo protein synthesis inhibition experiment using cycloheximide showed that the SIRT5(iso1) -specific C-terminus is necessary for maintaining the stability of SIRT5(iso1) . Moreover, genome sequence analysis from each organism examined indicated that SIRT5(iso2) is a primate-specific isoform. Taken together, these results indicate that human SIRT5 potentially controls various primate-specific functions via two isoforms with different intracellular localizations or stabilities.
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SIRT5 is present in the nucleus and cytoplasm in addition to mitochondria.
“Given that SIRT5 is present in the nucleus and cytoplasm in addition to mitochondria ((Matsushita et al. 2011))((Park et al. 2013))((Nishida et al. 2015)), it will be interesting to test whether SIRT5 modulates the activity of the urea cycle via targeting of both mitochondrial and cytosolic enzymes, or whether one compartment’s effects dominate.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Matsushita et al. 2011
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Nishida, Y., Rardin, M. J., Carrico, C., He, W., Sahu, A. K., Gut, P., Najjar, R., Fitch, M., Hellerstein, M., Gibson, B. W., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.05.022 · Cited by 481 · see citing works
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- Authors
- Matsushita, N., Yonashiro, R., Ogata, Y., Sugiura, A., Nagashima, S., Fukuda, T., Inatome, R., & Yanagi, S.
- Affiliations
- Tokyo University of Pharmacy and Life Sciences (JP)
- Corresponding author
- Yanagi, Shigeru
- Venue
- Genes to Cells
- Publisher
- Wiley
- Published
- 2010-12-09
- Volume
- 16
- Issue
- 2
- Pages
- 190-202
- ISSN
- 1356-9597 (ISSN-L)
- OpenAlex
- W1513259889
- Cited by
- 106
- References
- 51
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 6 · 2023: 10 · 2022: 9 · 2021: 13 · 2020: 7 · 2019: 8 · 2018: 10 · 2017: 8 · 2016: 8 · 2015: 7 · 2014: 6 · 2013: 4 · 2012: 2
- FWCI
- 0.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes to Cells (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Keio University
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- SIRT5, sirtuins, alternative splicing, protein isoforms, mitochondrial targeting, protein stability, subcellular localization
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Enzyme Stability, HeLa Cells, Humans, Mitochondria, Molecular Sequence Data, Nuclear Proteins, Primates, Conserved Sequence, Alternative Splicing, Protein Isoforms, Sirtuins, HEK293 Cells
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