Online ISSN: 1945-4589
Learn about our FREE Post-Publication Promotion Services
Research Perspective Volume 12, Issue 5 pp 4673—4677

The flip side of sirtuins: the emerging roles of protein acetyltransferases in aging

Prabakaran Nagarajan1, , Mark R. Parthun1, ,

  • 1 Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210, USA

Received: January 13, 2020       Accepted: March 7, 2020       Published: March 13, 2020      

https://doi.org/10.18632/aging.102949
How to Cite

Copyright © 2020 Nagarajan and Parthun. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Protein N-ε-lysine acetylation is is an important post-translational modification that plays critical roles in the regulation of many cellular processes. A role for this modification in the process of aging goes back two decades to the discovery that the yeast NAD+-dependent histone deacetylase Sir2 regulates lifespan in yeast. While the Sirtuin family of protein deacetylases has been intensively studied in many model systems and is definitively linked to aging, the enzymes responsible for protein acetylation, protein acetyltransferases (KATs), have not received a similar level of attention. However, a series of recent studies have directly explored the role of specific KATs in aging. These studies have shown that modulation of KAT activity can influence cellular pathways important for aging and directly effect organismal lifespan.

The level of acetylation on a given protein is the result of a balance in the activity of opposing families of enzymes, protein lysine acetyltransferases that attach the acetyl moieties and protein deacetylases that remove the acetyl groups. The idea that protein acetylation plays an important role in the regulation of aging began with the pioneering work on the Sirtuin family of NAD+-dependent protein deacetylases. Levels of the yeast histone deacetylase Sir2 correlated with lifespan as increased levels of Sir2 increasing lifespan and deletion of Sir2 decreasing lifespan in S. cerevisiae [1,2]. Subsequent studies in model organisms such as, flies, worms and mice, showed that genetic or pharmacological modulation of Sirtuin activity influenced lifespan [3–9]. While a role for protein deacetylases in aging is firmly established, the enzymes on the other side of the equation, the protein lysine acetyltransferases, have not received a proportionate share of research into understanding their potential roles in the regulation of aging.

Protein N-ε-lysine acetyltransferases (KATs) are a diverse family of enzymes [10]. While many of these enzymes were originally identified as histone acetyltransferases, it is now clear that most, if not all, have multiple substrates. From a broad perspective, it is not surprising that KATs are likely to play key roles in the aging process. KATs modify proteins involved in many cellular processes including those linked to the hallmarks of aging [11]. A number of recent studies have directly examined specific KATs for a link to aging.

Hat1

Hat1 was the first KAT identified (also known as Kat1). It was originally isolated based on its role in the evolutionarily conserved diacetylation of newly synthesized histone H4 during the process of chromatin assembly [12,13]. While Hat1 is essential for viability in mice, a link between Hat1 and aging was identified by the analysis of Hat1+/- heterozygotes [14]. Hat1+/- animals are largely normal at birth but develop a number of phenotypes suggestive of early nset aging within their first year. These phenotypes include lordokyphosis, hind limb paralysis, muscle atrophy, loss of subcutaneous fat and tumor development. Strikingly, Hat1+/- mice have a significantly shortened lifespan of approximately 69 weeks compared to greater than 120 weeks for wild type animals. A direct role for Hat1 in the normal aging process is suggested by the observation that Hat1 expression, at both the mRNA and protein levels, decreases dramatically with age in wild type animals [15]. Although they have opposite effects on protein acetylation, it is intriguing that decreases in Hat1 activity have a similar effect on aging as decreases in Sirtuin activity. This is consistent with observations in yeast where deletions of Hat1 and Sir2 both lead to loss of telomeric silent chromatin structure [16]. The mechanism(s) by which Hat1 influences aging are not clear as Hat1 is involved in multiple cellular process important to aging at the cellular level. These include transcriptional regulation, DNA damage repair, genome stability and mitochondrial function [14,15,17–21]. In addition, a recent proteomic analysis indicates that Hat1 influences the acetylation state of a number of proteins known to be important for mammalian aging (Agudelo Garcia,et al, bioRxiv doi: https://doi.org/10.1101/825539).

CBP/p300

The paralogs CBP and p300 are transcriptional coactivators that possess protein acetyltransferase activity. CBP and p300 participate in multiple signaling pathways and are key factors in disease states such as cancer and neurodegeneration [22]. Several lines of evidence indicate that these KATs are also critical factors in several aspects of aging. First, p300 has been shown to be an important regulator of cellular senescence, which is an important driver of decreased tissue function during aging [23–25]. Second, acetylation of several proteins by p300 and/or CBP have been shown to be involved to be involved in aging-related processes, including WRN, C/EBPα and TAU [26–29]. Third, lifespan extension in model organisms, through either dietary/caloric restriction or pharmacological mimetics of dietary restriction, requires CBP and p300 [30–36]. Finally, studies in C. elegans have directly demonstrated that reduced expression of CBP or p300 shortens lifespan [37–40].

CLOCK

The KAT protein CLOCK is an integral component of the of the molecular clock that maintains circadian rhythms [41]. Circadian rhythms play an important role in a variety of processes, including stress responses, immune function, metabolism and sleep regulation. Disruptions of the circadian rhythms can have serious pathological consequences including improper metabolism, sleep disorders, cardiovascular disease and neurodegenerative diseases [42–44]. Mutational analyses in flies and mice have indicated that loss of CLOCK activity is linked to age-dependent tissue defects. In flies, CLOCK is required in pacemaker neurons to prevent premature locomotor aging. Interestingly, this effect is independent of the role of CLOCK in the circadian rhythm [45]. In mice, expression of a CLOCK mutant lacking exon 19 (ClockΔ19/Δ19) results in accelerated aging in both the heart and liver [46,47].

Chameau

Chameau (Chm) is the D. melanogaster homolog of Hbo1 (KAT7). Hbo1 is a MYST family acetyltransferase that functions in regulating gene expression and DNA replication [48]. In a recent study examining changes in metabolism and histone acetylation during aging, it was found that flies with a catalytically inactive Chm mutation had a significant increase in lifespan. It was proposed that the Chm mutation extended lifespan through the attenuation of transcriptional changes associated with aging [49].

These recent studies have now shown that several KATs are directly linked to the aging process and that genetic and pharmacological manipulation of KATs can influence lifespan. Our understanding of the link between KATs and aging clearly has a long way to go to match our understanding of Sirtuins. Important questions that need to be addressed include determining the relevant aging-related cellular processes that each KAT functions in and identifying aging-relevant substrates for each KAT. It will take intensive investigation to decipher the molecular mechanisms underlying the influence of KATs on aging and lifespan.

Conflicts of Interest

The authors have no conflict of interests to declare.

Funding

This work was supported by a grant from the National Institutes of Health (R01 GM062970 to M.R.P.).

References

  • 1. Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999; 13:2570–80. https://doi.org/10.1101/gad.13.19.2570 [PubMed]
  • 2. Kim S, Benguria A, Lai CY, Jazwinski SM. Modulation of life-span by histone deacetylase genes in Saccharomyces cerevisiae. Mol Biol Cell. 1999; 10:3125–36. https://doi.org/10.1091/mbc.10.10.3125 [PubMed]
  • 3. Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature. 2001; 410:227–30. https://doi.org/10.1038/35065638 [PubMed]
  • 4. Rogina B, Helfand SL. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci USA. 2004; 101:15998–6003. https://doi.org/10.1073/pnas.0404184101 [PubMed]
  • 5. Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G, Nahum L, Bar-Joseph Z, Cohen HY. The sirtuin SIRT6 regulates lifespan in male mice. Nature. 2012; 483:218–21. https://doi.org/10.1038/nature10815 [PubMed]
  • 6. Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM, Mills KD, Patel P, Hsu JT, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006; 124:315–29. https://doi.org/10.1016/j.cell.2005.11.044 [PubMed]
  • 7. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004; 430:686–89. https://doi.org/10.1038/nature02789 [PubMed]
  • 8. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003; 425:191–96. https://doi.org/10.1038/nature01960 [PubMed]
  • 9. Bonkowski MS, Sinclair DA. Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat Rev Mol Cell Biol. 2016; 17:679–90. https://doi.org/10.1038/nrm.2016.93 [PubMed]
  • 10. Lee KK, Workman JL. Histone acetyltransferase complexes: one size doesn’t fit all. Nat Rev Mol Cell Biol. 2007; 8:284–95. https://doi.org/10.1038/nrm2145 [PubMed]
  • 11. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013; 153:1194–217. https://doi.org/10.1016/j.cell.2013.05.039 [PubMed]
  • 12. Parthun MR, Widom J, Gottschling DE. The major cytoplasmic histone acetyltransferase in yeast: links to chromatin replication and histone metabolism. Cell. 1996; 87:85–94. https://doi.org/10.1016/S0092-8674(00)81325-2 [PubMed]
  • 13. Kleff S, Andrulis ED, Anderson CW, Sternglanz R. Identification of a gene encoding a yeast histone H4 acetyltransferase. J Biol Chem. 1995; 270:24674–77. https://doi.org/10.1074/jbc.270.42.24674 [PubMed]
  • 14. Nagarajan P, Ge Z, Sirbu B, Doughty C, Agudelo Garcia PA, Schlederer M, Annunziato AT, Cortez D, Kenner L, Parthun MR. Histone acetyl transferase 1 is essential for mammalian development, genome stability, and the processing of newly synthesized histones H3 and H4. PLoS Genet. 2013; 9:e1003518. https://doi.org/10.1371/journal.pgen.1003518 [PubMed]
  • 15. Nagarajan P, Agudelo Garcia PA, Iyer CC, Popova LV, Arnold WD, Parthun MR. Early-onset aging and mitochondrial defects associated with loss of histone acetyltransferase 1 (Hat1). Aging Cell. 2019; 18:e12992. https://doi.org/10.1111/acel.12992 [PubMed]
  • 16. Kelly TJ, Qin S, Gottschling DE, Parthun MR. Type B histone acetyltransferase Hat1p participates in telomeric silencing. Mol Cell Biol. 2000; 20:7051–58. https://doi.org/10.1128/MCB.20.19.7051-7058.2000 [PubMed]
  • 17. Agudelo Garcia PA, Hoover ME, Zhang P, Nagarajan P, Freitas MA, Parthun MR. Identification of multiple roles for histone acetyltransferase 1 in replication-coupled chromatin assembly. Nucleic Acids Res. 2017; 45:9319–35. https://doi.org/10.1093/nar/gkx545 [PubMed]
  • 18. Qin S, Parthun MR. Histone H3 and the histone acetyltransferase Hat1p contribute to DNA double-strand break repair. Mol Cell Biol. 2002; 22:8353–65. https://doi.org/10.1128/MCB.22.23.8353-8365.2002 [PubMed]
  • 19. Sadler AJ, Suliman BA, Yu L, Yuan X, Wang D, Irving AT, Sarvestani ST, Banerjee A, Mansell AS, Liu JP, Gerondakis S, Williams BR, Xu D. The acetyltransferase HAT1 moderates the NF-κB response by regulating the transcription factor PLZF. Nat Commun. 2015; 6:6795. https://doi.org/10.1038/ncomms7795 [PubMed]
  • 20. Gruber JJ, Geller B, Lipchik AM, Chen J, Salahudeen AA, Ram AN, Ford JM, Kuo CJ, Snyder MP. HAT1 Coordinates Histone Production and Acetylation via H4 Promoter Binding. Mol Cell. 2019; 75:711–724.e5. https://doi.org/10.1016/j.molcel.2019.05.034 [PubMed]
  • 21. Marin TL, Gongol B, Zhang F, Martin M, Johnson DA, Xiao H, Wang Y, Subramaniam S, Chien S, Shyy JY. AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1. Sci Signal. 2017; 10:10. https://doi.org/10.1126/scisignal.aaf7478 [PubMed]
  • 22. Attar N, Kurdistani SK. Exploitation of EP300 and CREBBP Lysine Acetyltransferases by Cancer. Cold Spring Harb Perspect Med. 2017; 7:7. https://doi.org/10.1101/cshperspect.a026534 [PubMed]
  • 23. Prieur A, Besnard E, Babled A, Lemaitre JM. p53 and p16(INK4A) independent induction of senescence by chromatin-dependent alteration of S-phase progression. Nat Commun. 2011; 2:473. https://doi.org/10.1038/ncomms1473 [PubMed]
  • 24. Li Y, Zhong H, Wu M, Tan B, Zhao L, Yi Q, Xu X, Pan H, Bi Y, Yang K. Decline of p300 contributes to cell senescence and growth inhibition of hUC-MSCs through p53/p21 signaling pathway. Biochem Biophys Res Commun. 2019; 515:24–30. https://doi.org/10.1016/j.bbrc.2019.05.061 [PubMed]
  • 25. Sen P, Lan Y, Li CY, Sidoli S, Donahue G, Dou Z, Frederick B, Chen Q, Luense LJ, Garcia BA, Dang W, Johnson FB, Adams PD, et al. Histone Acetyltransferase p300 Induces De Novo Super-Enhancers to Drive Cellular Senescence. Mol Cell. 2019; 73:684–698.e8. https://doi.org/10.1016/j.molcel.2019.01.021 [PubMed]
  • 26. Min SW, Chen X, Tracy TE, Li Y, Zhou Y, Wang C, Shirakawa K, Minami SS, Defensor E, Mok SA, Sohn PD, Schilling B, Cong X, et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med. 2015; 21:1154–62. https://doi.org/10.1038/nm.3951 [PubMed]
  • 27. Zaini MA, Müller C, de Jong TV, Ackermann T, Hartleben G, Kortman G, Gührs KH, Fusetti F, Krämer OH, Guryev V, Calkhoven CF. A p300 and SIRT1 Regulated Acetylation Switch of C/EBPα Controls Mitochondrial Function. Cell Rep. 2018; 22:497–511. https://doi.org/10.1016/j.celrep.2017.12.061 [PubMed]
  • 28. Muftuoglu M, Kusumoto R, Speina E, Beck G, Cheng WH, Bohr VA. Acetylation regulates WRN catalytic activities and affects base excision DNA repair. PLoS One. 2008; 3:e1918. https://doi.org/10.1371/journal.pone.0001918 [PubMed]
  • 29. Li K, Casta A, Wang R, Lozada E, Fan W, Kane S, Ge Q, Gu W, Orren D, Luo J. Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation. J Biol Chem. 2008; 283:7590–98. https://doi.org/10.1074/jbc.M709707200 [PubMed]
  • 30. Vora M, Shah M, Ostafi S, Onken B, Xue J, Ni JZ, Gu S, Driscoll M. Deletion of microRNA-80 activates dietary restriction to extend C. elegans healthspan and lifespan. PLoS Genet. 2013; 9:e1003737. https://doi.org/10.1371/journal.pgen.1003737 [PubMed]
  • 31. Madeo F, Pietrocola F, Eisenberg T, Kroemer G. Caloric restriction mimetics: towards a molecular definition. Nat Rev Drug Discov. 2014; 13:727–40. https://doi.org/10.1038/nrd4391 [PubMed]
  • 32. Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, Harger A, Schipke J, Zimmermann A, Schmidt A, Tong M, Ruckenstuhl C, Dammbrueck C, et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016; 22:1428–38. https://doi.org/10.1038/nm.4222 [PubMed]
  • 33. Pietrocola F, Lachkar S, Enot DP, Niso-Santano M, Bravo-San Pedro JM, Sica V, Izzo V, Maiuri MC, Madeo F, Mariño G, Kroemer G. Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ. 2015; 22:509–16. https://doi.org/10.1038/cdd.2014.215 [PubMed]
  • 34. Tezil T, Chamoli M, Ng CP, Simon RP, Butler VJ, Jung M, Andersen J, Kao AW, Verdin E. Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy. NPJ Aging Mech Dis. 2019; 5:7. https://doi.org/10.1038/s41514-019-0037-7 [PubMed]
  • 35. Wang J, Gallagher D, DeVito LM, Cancino GI, Tsui D, He L, Keller GM, Frankland PW, Kaplan DR, Miller FD. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell. 2012; 11:23–35. https://doi.org/10.1016/j.stem.2012.03.016 [PubMed]
  • 36. Moreno CL, Mobbs CV. Epigenetic mechanisms underlying lifespan and age-related effects of dietary restriction and the ketogenic diet. Mol Cell Endocrinol. 2017; 455:33–40. https://doi.org/10.1016/j.mce.2016.11.013 [PubMed]
  • 37. Zhou L, He B, Deng J, Pang S, Tang H. Histone acetylation promotes long-lasting defense responses and longevity following early life heat stress. PLoS Genet. 2019; 15:e1008122. https://doi.org/10.1371/journal.pgen.1008122 [PubMed]
  • 38. Ganner A, Gerber J, Ziegler AK, Li Y, Kandzia J, Matulenski T, Kreis S, Breves G, Klein M, Walz G, Neumann-Haefelin E. CBP-1/p300 acetyltransferase regulates SKN-1/Nrf cellular levels, nuclear localization, and activity in C. elegans. Exp Gerontol. 2019; 126:110690. https://doi.org/10.1016/j.exger.2019.110690 [PubMed]
  • 39. Cai H, Dhondt I, Vandemeulebroucke L, Vlaeminck C, Rasulova M, Braeckman BP. CBP-1 Acts in GABAergic Neurons to Double Life Span in Axenically Cultured Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci. 2019; 74:1198–205. https://doi.org/10.1093/gerona/glx206 [PubMed]
  • 40. Zhang M, Poplawski M, Yen K, Cheng H, Bloss E, Zhu X, Patel H, Mobbs CV. Role of CBP and SATB-1 in aging, dietary restriction, and insulin-like signaling. PLoS Biol. 2009; 7:e1000245. https://doi.org/10.1371/journal.pbio.1000245 [PubMed]
  • 41. Doi M, Hirayama J, Sassone-Corsi P. Circadian regulator CLOCK is a histone acetyltransferase. Cell. 2006; 125:497–508. https://doi.org/10.1016/j.cell.2006.03.033 [PubMed]
  • 42. Dierickx P, Van Laake LW, Geijsen N. Circadian clocks: from stem cells to tissue homeostasis and regeneration. EMBO Rep. 2018; 19:18–28. https://doi.org/10.15252/embr.201745130 [PubMed]
  • 43. Logan RW, McClung CA. Rhythms of life: circadian disruption and brain disorders across the lifespan. Nat Rev Neurosci. 2019; 20:49–65. https://doi.org/10.1038/s41583-018-0088-y [PubMed]
  • 44. Terzibasi-Tozzini E, Martinez-Nicolas A, Lucas-Sánchez A. The clock is ticking. Ageing of the circadian system: from physiology to cell cycle. Semin Cell Dev Biol. 2017; 70:164–76. https://doi.org/10.1016/j.semcdb.2017.06.011 [PubMed]
  • 45. Vaccaro A, Issa AR, Seugnet L, Birman S, Klarsfeld A. Drosophila Clock Is Required in Brain Pacemaker Neurons to Prevent Premature Locomotor Aging Independently of Its Circadian Function. PLoS Genet. 2017; 13:e1006507. https://doi.org/10.1371/journal.pgen.1006507 [PubMed]
  • 46. Alibhai FJ, LaMarre J, Reitz CJ, Tsimakouridze EV, Kroetsch JT, Bolz SS, Shulman A, Steinberg S, Burris TP, Oudit GY, Martino TA. Disrupting the key circadian regulator CLOCK leads to age-dependent cardiovascular disease. J Mol Cell Cardiol. 2017; 105:24–37. https://doi.org/10.1016/j.yjmcc.2017.01.008 [PubMed]
  • 47. Yuan G, Hua B, Cai T, Xu L, Li E, Huang Y, Sun N, Yan Z, Lu C, Qian R. Clock mediates liver senescence by controlling ER stress. Aging (Albany NY). 2017; 9:2647–65. https://doi.org/10.18632/aging.101353 [PubMed]
  • 48. Lan R, Wang Q. Deciphering structure, function and mechanism of lysine acetyltransferase HBO1 in protein acetylation, transcription regulation, DNA replication and its oncogenic properties in cancer. Cell Mol Life Sci. 2020; 77:637–49. https://doi.org/10.1007/s00018-019-03296-x [PubMed]
  • 49. Peleg S, Feller C, Forne I, Schiller E, Sévin DC, Schauer T, Regnard C, Straub T, Prestel M, Klima C, Schmitt Nogueira M, Becker L, Klopstock T, et al. Life span extension by targeting a link between metabolism and histone acetylation in Drosophila. EMBO Rep. 2016; 17:455–69. https://doi.org/10.15252/embr.201541132 [PubMed]
Download PDF
Corresponding Author

Mark R. Parthun
parthun.1@osu.edu

Keywords
acetyltransferase acetylation aging Sirtuin KAT
Paper Sections