Abstract
Sirtuins are a family of deacetylases (Class III histone deacetylases) with evolutionarily conserved functions in cellular metabolism and chromatin regulation. Out of the seven human Sirtuins, the function of Sirt2 is the least understood. The purpose of the present study was to investigate the role of Sir2A, a homolog of human Sirt2 in Dictyostelium discoideum (Dd), a lower eukaryote. We created both overexpressing and deletion strains of Ddsir2A to analyse its functions. We observed sir2A mRNA expression throughout development and the transcript was present in the prespore/spore region of multicellular structures developed. They show a preference towards prestalk/stalk pathway when co-developed with wild-type cells during chimera formation. Deletion strain showed a multi-tipped phenotype, decrease in cell proliferation and inhibition of autophagy. In conclusion, our results show low cAMP levels, reduced cell-adhesion, weak cell migration and impaired autophagy to be responsible for the phenotype shown by the null cells. This study provides new insights into the functions of Ddsir2A.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bae NS, Swanson MJ, Vassilev A and Howard BH 2004 Human histone deacetylase SIRT2 interacts with the homeobox transcription factor HOXA10. J. Biochem. 135 695–700
Bannister AJ and Kouzarides T 2011 Regulation of chromatin by histone modifications. Cell Res. 21 381–395
Borra MT, O’Neill FJ, Jackson MD, Marshall B, Verdin E, Foltz KR and Denu JM 2002 Conserved enzymatic production and biological effect of O-acetyl-ADP-ribose by silent information regulator 2-like NAD+-dependent deacetylases. J. Biol. Chem. 277 12632–12641
Bosch-Presegué L and Vaquero A 2011 The Dual Role of Sirtuins in Cancer. Genes Cancer 2 648–662
Calvo-Garrido J, Carilla-Latorre S, Kubohara Y, Santos-Rodrigo N, Mesquita A, Soldati T, Golstein P and Escalante R 2010 Autophagy in Dictyostelium: genes and pathways, cell death and infection. Autophagy 6 686-701
Chalkiadaki A and Guarente L 2012 Sirtuins mediate mammalian metabolic responses to nutrient availability. Nat. Rev. Endocrinol. 8 287–296
Dryden SC, Nahhas FA, Nowak JE, Goustin AS and Tainsky MA 2003 Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol. Cell. Biol. 23 3173–3185
Fyre RA 2000 Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 273 793-798
Gamsjaeger R, Liew CK, Loughlin FE, Crossley M and Mackay JP 2007 Sticky fingers: zinc-fingers as protein-recognition motifs. Trends Biochem. Sci. 32 63–70
Gosain A, Lohia R, Shrivastava A and Saran S 2012 Identification and characterization of peptide: N- glycanase from Dictyostelium discoideum. BMC Biochem. 13 9
Hall TMT 2005 Multiple modes of RNA recognition by zinc finger proteins. Curr. Opin. Struct. Biol. 15 367–373
Hiratsuka M, Inoue T, Toda T, Kimura N, Shirayoshi Y, Kamitani H, Watanabe T, Ohama E, Tahimic CGT, Kurimasa A and Oshimura M 2003 Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene. Biochem. Biophys. Res. Commun. 309 558–566
Katayama T and Yasukawa H 2008 Developmental and spatial expression of sir2 gene in the cellular slime mold Dictyostelium discoideum. Microbes Environ. 23 40–43
Klug A 1999 Zinc finger peptides for the regulation of gene expression. J. Mol. Biol. 293 215–218
Li X and Kazgan N 2011 Mammalian Sirtuins and Energy Metabolism. Int. J. Biol. Sci. 7 575–587
Lohia R, Jain P, Jain M, Burma PK, Shrivastava A and Saran S 2017 Dictyostelium discoideum Sir2D modulates cell-type specific gene expression and is involved in autophagy. Int. J. Dev. Biol. 61 95-104
Ma L, Maruwge W, Strambi A, D’Arcy P, Pellegrini P, Kis L, de Milito A, Lain S and Brodin B 2014 SIRT1 and SIRT2 inhibition impairs pediatric soft tissue sarcoma growth. Cell Death Dis. 5 e1483
Martínez-Redondo P and Vaquero A 2013 The diversity of histone versus nonhistone sirtuin substrates. Genes Cancer 4 148–163
Maurya R, Kumar R and Saran S 2017 Dictyostelium AMPK regulates aggregate-size and cell-type patterning. Open Biol. 7 170055
Mishra H, Bhadoriya P and Saran S 2017 Disruption of homeobox containing gene, hbx9 results in the deregulation of prestalk cell patterning in Dictyostelium discoideum. Differentiation 94 27–36
Mizushima N and Levine B 2010 Autophagy in mammalian development and differentiation. Nat. Cell Biol. 12 823–830
North BJ and Verdin E 2004 Sirtuins: Sir2-related NAD-dependent protein deacetylases. Genome Biol. 5 224
North BJ and Verdin E 2007 Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis. PLoS One 2 e784
North BJ, Marshall BL, Borra MT, Denu JM and Verdin E 2003 The human Sir2 ortholog, SIRT2, is an NAD+ dependent tubulin deacetylase. Mol. Cell. 11 437–444
Otto GP, Wu MY, Kazgan N, Anderson OR and Kessin RH 2004 Dictyostelium macroautophagy mutants vary in the severity of their developmental defects. J. Biol. Chem. 279 15621–15629
Perrod S, Cockell MM, Laroche T, Renauld H, Ducrest A L, Bonnard C and Gasser SM 2001 A cytosolic NAD-dependent deacetylase, Hst2p, can modulate nucleolar and telomeric silencing in yeast. EMBO J. 20 197–209
Sack MN and Finkel T 2012 Mitochondrial metabolism, sirtuins, and aging. Cold Spring Harb. Perspect. Biol. 4 a013102
Schaap P 2011 Evolution of developmental cyclic AMP signalling in the Dictyostelia from an amoebozoan stress response. Dev. Growth Differ. 53 452–462
Serrano L, Martínez-Redondo P, Marazuela-Duque A, Vazquez BN, Dooley SJ, Voigt P, Beck DB, Kane-Goldsmith N, Tong Q, Rabanal RM, Fondevila D, Muñoz P, Krüger M, Tischfield JA and Vaquero A 2013 The tumor suppressor Sirt2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation. Genes Dev. 27 639–653
Swer PB, Lohia R, Saran S 2014 Analysis of rapamycin induced autophagy in Dictyostelium discoideum Indian J Exp Biol 52:295-304
Vaquero A, Scher MB, Lee DH, Sutton A, Cheng HL, Alt FW, Serrano L, Sternglanz R and Reinberg D 2006 Sirt2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev. 20 1256–1261
Acknowledgements
SS thanks DST (SR/SO/BB-18/2008) and ICMR (54/41/CFP/GER/2011-NCD-II) for research grants. Partial research grants from DST-PURSE, UGC networking, UPE-II and DST-FISTII are also acknowledged. RL, PJ, HM and MJ thank CSIR, DST-INSPIRE, CSIR and DBT for fellowships, respectively.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by ULLAS KOLTHUR-SEETHARAM.
Corresponding editor: Ullas Kolthur-Seetharam
Rakhee Lohia and Punita Jain: Equal authorship.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Lohia, R., Jain, P., Jain, M. et al. Deletion of Dictyostelium discoideum Sir2A impairs cell proliferation and inhibits autophagy. J Biosci 43, 351–364 (2018). https://doi.org/10.1007/s12038-018-9753-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12038-018-9753-6