Sirtinol Supresses Trophozoites Proliferation and Encystation of Acanthamoeba via Inhibition of Sirtuin Family Protein
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
The encystation of Acanthamoeba leads to the development of metabolically inactive and dormant cysts from vegetative trophozoites under unfavorable conditions. These cysts are highly resistant to anti-Acanthamoeba drugs and biocides. Therefore, the inhibition of encystation would be more effective in treating Acanthamoeba infection. In our previous study, a sirtuin family protein—Acanthamoeba silent-information regulator 2-like protein (AcSir2)—was identified, and its expression was discovered to be critical for Acanthamoeba castellanii proliferation and encystation. In this study, to develop Acanthamoeba sirtuin inhibitors, we examine the effects of sirtinol, a sirtuin inhibitor, on trophozoite growth and encystation. Sirtinol inhibited A. castellanii trophozoites proliferation (IC50=61.24 μM). The encystation rate of cells treated with sirtinol significantly decreased to 39.8% (200 μM sirtinol) after 24 hr of incubation compared to controls. In AcSir2-overexpressing cells, the transcriptional level of cyst-specific cysteine protease (CSCP), an Acanthamoeba cysteine protease involved in the encysting process, was 11.6- and 88.6-fold higher at 48 and 72 hr after induction of encystation compared to control. However, sirtinol suppresses CSCP transcription, resulting that the undegraded organelles and large molecules remained in sirtinol-treated cells during encystation. These results indicated that sirtinol sufficiently inhibited trophozoite proliferation and encystation, and can be used to treat Acanthamoeba infections.
Abstract
The encystation of Acanthamoeba leads to the development of metabolically inactive and dormant cysts from vegetative trophozoites under unfavorable conditions. These cysts are highly resistant to anti-Acanthamoeba drugs and biocides. Therefore, the inhibition of encystation would be more effective in treating Acanthamoeba infection. In our previous study, a sirtuin family protein—Acanthamoeba silent-information regulator 2-like protein (AcSir2)—was identified, and its expression was discovered to be critical for Acanthamoeba castellanii proliferation and encystation. In this study, to develop Acanthamoeba sirtuin inhibitors, we examine the effects of sirtinol, a sirtuin inhibitor, on trophozoite growth and encystation. Sirtinol inhibited A. castellanii trophozoites proliferation (IC50=61.24 μM). The encystation rate of cells treated with sirtinol significantly decreased to 39.8% (200 μM sirtinol) after 24 hr of incubation compared to controls. In AcSir2-overexpressing cells, the transcriptional level of cyst-specific cysteine protease (CSCP), an Acanthamoeba cysteine protease involved in the encysting process, was 11.6- and 88.6-fold higher at 48 and 72 hr after induction of encystation compared to control. However, sirtinol suppresses CSCP transcription, resulting that the undegraded organelles and large molecules remained in sirtinol-treated cells during encystation. These results indicated that sirtinol sufficiently inhibited trophozoite proliferation and encystation, and can be used to treat Acanthamoeba infections.
참고문헌 (32)
- Khan NA, "Acanthamoeba: biology and pathogenesis" (2015), Caister Academic Press
- Walochnik J, "Molecular parasitology: protozoan parasites and their molecules" (2016), Springer
- D. LLOYD, "Encystation in Acanthamoeba castellanii: Development of Biocide Resistance1", The Journal of Eukaryotic Microbiology, 48(1), pp.11~16 (2001), Wiley[DOI]
- Gus Tomlinson, "Isolation of cellulose from the cyst wall of a soil amoeba", Biochimica et Biophysica Acta, 63(1), pp.194~200 (1962), Elsevier BV[DOI]
- Robert A. Weisman, "DIFFERENTIATION IN <i>ACANTHAMOEBA CASTELLANII<", i>, 1976, pp.30(1), 189~219[DOI]
- Francine Marciano-Cabral, "Acanthamoeba spp. as agents of disease in humans", Clinical Microbiology Reviews, 16(2), pp.273~307 (2003), American Society for Microbiology[DOI]
- So-Young Joo, "The role of the Acanthamoeba castellanii Sir2-like protein in the growth and encystation of Acanthamoeba", Parasites & Vectors, 13(1), pp.368~ (2020), Springer Science and Business Media LLC[DOI]
- Shin-ichiro Imai, "Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase", Nature, 403(6771), pp.795~800 (2000), Springer Science and Business Media LLC[DOI]
- Hung-Chun Chang, "SIRT1 and other sirtuins in metabolism", Trends in Endocrinology & Metabolism, 25(3), pp.138~145 (2014), Elsevier BV[DOI]
- Joseph Landry, "The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases", Proceedings of the National Academy of Sciences, 97(11), pp.5807~5811 (2000), Proceedings of the National Academy of Sciences[DOI]
- Eriko Michishita, "Evolutionarily Conserved and Nonconserved Cellular Localizations and Functions of Human SIRT Proteins", Molecular Biology of the Cell, 16(10), pp.4623~4635 (2005), American Society for Cell Biology (ASCB)[DOI]
- Sung Chan Kim, "Substrate and Functional Diversity of Lysine Acetylation Revealed by a Proteomics Survey", Molecular Cell, 23(4), pp.607~618 (2006), Elsevier BV[DOI]
- Marcia C. Haigis, "Mammalian Sirtuins: Biological Insights and Disease Relevance", Annual Review of Pathology: Mechanisms of Disease, 5(1), pp.253~295 (2010), Annual Reviews[DOI]
- G. S. VISVESVARA, "Comparative Studies on Related Free-Living and Pathogenic Amebae With Special Reference to<i>Acanthamoeba<", i>, 1975, pp.22(2), 245~256[DOI]
- Blair Bowers, "THE FINE STRUCTURE OF ACANTHAMOEBA CASTELLANII (NEFF STRAIN)", Journal of Cell Biology, 41(3), pp.786~805 (1969), Rockefeller University Press[DOI]
- Wolfgang Nellen, "Actin genes and actin messenger RNA in Acanthamoeba castellanii", Journal of Molecular Biology, 159(1), pp.1~18 (1982), Elsevier BV[DOI]
- Yu-Ran Lee, "Essential Role for an M17 Leucine Aminopeptidase in Encystation of Acanthamoeba castellanii", PLOS ONE, 10(6), pp.e0129884~ (2015), Public Library of Science (PLoS)[DOI]
- Mazur T, "Value of the color test in assessing the viability of cysts of Acanthamoeba sp", Wiad Parazytol, 35, pp.11~17 (1989)
- Karina Picazarri, "Autophagy during proliferation and encystation in the protozoan parasite Entamoeba invadens", Infection and Immunity, 76(1), pp.278~288 (2008), American Society for Microbiology[DOI]
- Coulon C, "Resistance of Acanthamoeba cysts to disinfection treatments used in health care settings", J Clin Microbiol, 48, pp.2689~2697 (2010)[DOI]
- Eun-Kyung Moon, "Cysteine protease involving in autophagosomal degradation of mitochondria during encystation of Acanthamoeba", Molecular and Biochemical Parasitology, 185(2), pp.121~126 (2012), Elsevier BV[DOI]
- NeffRJ, "The biochemistry of amoebic encystment", Symp Soc Exp Biol, 23, pp.51~81 (1969)
- Ricky Dudley, "Cellulose biosynthesis pathway is a potential target in the improved treatment of Acanthamoeba keratitis", Applied Microbiology and Biotechnology, 75(1), pp.133~140 (2007), Springer Science and Business Media LLC[DOI]
- Su-Min Song, "Autophagy protein 16-mediated autophagy is required for the encystation of Acanthamoeba castellanii", Molecular and Biochemical Parasitology, 183(2), pp.158~165 (2012), Elsevier BV[DOI]
- In Hye Lee, "A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy", Proceedings of the National Academy of Sciences, 105(9), pp.3374~3379 (2008), Proceedings of the National Academy of Sciences[DOI]
- Mingming Zhang, "Sirtinol promotes PEPCK1 degradation and inhibits gluconeogenesis by inhibiting deacetylase SIRT2", Scientific Reports, 7(1), pp.7~ (2017), Springer Science and Business Media LLC[DOI]
- JING WANG, "Sirtinol, a class III HDAC inhibitor, induces apoptotic and autophagic cell death in MCF-7 human breast cancer cells", International Journal of Oncology, 41(3), pp.1101~1109 (2012), Spandidos Publications[DOI]
- HUA XU, "SIRT2 mediates multidrug resistance in acute myelogenous leukemia cells via ERK1", 2 signaling pathway, 2015, pp.48(2), 613~623[DOI]
- Gesine Hoffmann, "A Novel Sirtuin 2 (SIRT2) Inhibitor with p53-dependent Pro-apoptotic Activity in Non-small Cell Lung Cancer", Journal of Biological Chemistry, 289(8), pp.5208~5216 (2014), Elsevier BV[DOI]
- Richard W. Hanson, "Phosphoenolpyruvate Carboxykinase (GTP): the Gene and the Enzyme", Advances in Enzymology - and Related Areas of Molecular Biology, pp.203~281 (2006), John Wiley & Sons, Inc.[DOI]
- Colleen K. Nye, "Glyceroneogenesis Is the Dominant Pathway for Triglyceride Glycerol Synthesis in Vivo in the Rat", Journal of Biological Chemistry, 283(41), pp.27565~27574 (2008), Elsevier BV[DOI]
- R. L. Tannen, "Ammonia metabolism", American Journal of Physiology-Renal Physiology, 235(4), pp.F265~F277 (1978), American Physiological Society[DOI]