Silent information regulator protein 6 and autophagy in age-related macular degeneration_Chinese Journal of Ocular Fundus Diseases

Authors：

Feng Yiji , Luo Xueting ,  Sun Xiaodong

Department of Ophthalmology, The First People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200080, China;

Corresponding author：

Sun Xiaodong, Email: xdsun@sjtu.edu.cn

Keywords：

Sirtuins; Autophagy; Aging; Macular degeneration; Diabetic retinopathy

DOI：

10.3760/cma.j.issn.1005-1015.2018.02.026

Video：

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Age-related macular degeneration is one of the major causes of blindness in the elderly. As an important pathway of cell metabolism, autophagy maintains intracellular homeostasis through the degradation and recycle of damaged organelles and macromolecules. Understanding its mechanism may promote discoveries to delay aging process, reduce the incidence of age-related diseases. In mammals, silent information regulator protein 6 (SIRT6) plays its deacetylase and ribonucleotransferase activity in multiple signaling pathways, including inhibition of cellular senescence, tumorigenesis, metabolic diseases, regulating cellular lifespan. It has a significant impact on the structure and function of tissues and organs. SIRT6 regulates intracellular autophagy mainly through the insulin-like growth factor-protein kinase B-mammalian target of rapamycin, reducing the accumulation of toxic metabolites and cellular senescence. The function of SIRT6 in age-related macular degeneration need to be combined with the genetic background, pathogenesis, clinical manifestations and other aspects of the disease, and it is expected to be further studied in subsequent studies.

Citation： Feng Yiji, Luo Xueting, Sun Xiaodong. Silent information regulator protein 6 and autophagy in age-related macular degeneration. Chinese Journal of Ocular Fundus Diseases, 2018, 34(2): 198-201. doi: 10.3760/cma.j.issn.1005-1015.2018.02.026 Copy

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26.	Lyssiotis CA, Cantley LC. SIRT6 puts cancer metabolism in the driver’s seat[J]. Cell, 2012, 151(6): 1155-1156. DOI:10.1016/j.cell.2012.11.020.
27.	Cardus A, Uryga AK, Walters G, et al. SIRT6 protects human endothelial cells from DNA damage, telomere dysfunction, and senescence[J]. Cardiovasc Res, 2013, 97(3): 571-579. DOI:10.1093/cvr/cvs352.
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37.	Salminen A, Kaarniranta K, Kauppinen A. Inflammaging: disturbed interplay between autophagy and inflammasomes[J]. Aging, 2012, 4(3): 166-175.
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40.	Tanaka Y, Kume S, Kitada M, et al. Autophagy as a therapeutic target in diabetic nephropathy[J/OL]. Exp Diabetes Res, 2012, 2012: 628978[2011-10-19]. https://dx.doi.org/10.1155/2012/628978. DOI:10.1155/2012/628978.
41.	Wang W, Wang Q, Wan D, et al. Histone HIST1H1C/H1.2 regulates autophagy in the development of diabetic retinopathy[J]. Autophagy, 2017, 13(5): 941-954. DOI:10.1080/15548627.2017.1293768.
42.	Mao J, Xia Q, Liu C, et al. A critical role of Hrd1 in the regulation of optineurin degradation and aggresome formation[J]. Hum Mol Genet, 2017, 26(10): 1877-1889. DOI:10.1093/hmg/ddx096.
43.	Takasaka N, Araya J, Hara H, et al. Autophagy induction by SIRT6 through attenuation of insulin-like growth factor signaling is involved in the regulation of human bronchial epithelial cell senescence[J]. J Immunol, 2014, 192(3): 958-968. DOI:10.4049/jimmunol.1302341.

1. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy[J]. Dev Cell, 2004, 6(4): 463-477.
2. Yorimitsu T, Klionsky DJ. Autophagy: molecular machinery for self-eating[J]. Cell Death Differ, 2005, 12 Suppl 2: S1542-1552. DOI: 10.1038/sj.cdd.4401765.
3. Zhang J, Bai Y, Huang L, et al. Protective effect of autophagy on human retinal pigment epithelial cells against lipofuscin fluorophore A2E: implications for age-related macular degeneration[J/OL]. Cell Death Dis, 2015, 6: 1972[2015-11-12]. http://dx.doi.org/10.1038/cddis.2015.330. DOI:10.1038/cddis.2015.330.
4. Liu J, Copland DA, Theodoropoulou S, et al. Impairing autophagy in retinal pigment epithelium leads to inflammasome activation and enhanced macrophage-mediated angiogenesis[J/OL]. Sci Rep, 2016, 6: 20639[2016-02-05]. http://dx.doi.org/10.1038/srep20639. DOI:10.1038/srep20639.
5. Jia G, Su L, Singhal S, et al. Emerging roles of SIRT6 on telomere maintenance, DNA repair, metabolism and mammalian aging[J]. Mol Cell Biochem, 2012, 364(1-2): 345-350. DOI:10.1007/s11010-012-1236-8.
6. Kanfi Y, Naiman S, Amir G, et al. The sirtuin SIRT6 regulates lifespan in male mice[J]. Nature, 2012, 483(7388): 218-221. DOI:10.1038/nature10815.
7. Yu SS, Cai Y, Ye JT, et al. Sirtuin 6 protects cardiomyocytes from hypertrophy in vitro via inhibition of NF-kappaB-dependent transcriptional activity[J]. Br J Pharmacol, 2013, 168(1): 117-128. DOI:10.1111/j.1476-5381.2012.01903.x.
8. Ban N, Ozawa Y, Inaba T, et al. Light-dark condition regulates sirtuin mRNA levels in the retina[J]. Exp Gerontol, 2013, 48(11): 1212-1217. DOI:10.1016/j.exger.2013.04.010.
9. Orellana ME, Quezada C, Maloney SC, et al. Expression of SIRT2 and SIRT6 in retinoblastoma[J]. Ophthalmic Res, 2015, 53(2): 100-108. DOI:10.1159/000368718.
10. Ravikumar B, Futter M, Jahreiss L, et al. Mammalian macroautophagy at a glance[J]. J Cell Sci, 2009, 122(Pt 11): 1707-1711. DOI:10.1242/jcs.031773.
11. Levine B, Kroemer G. Autophagy in the pathogenesis of disease[J]. Cell, 2008, 132(1): 27-42.
12. Jung CH, Jun CB, Ro SH, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery[J]. Mol Biol Cell, 2009, 20(7): 1992-2003. DOI:10.1091/mbc.E08.
13. Li X, He L, Che KH, et al. Imperfect interface of Beclin1 coiled-coil domain regulates homodimer and heterodimer formation with Atg14L and UVRAG[J/OL]. Nat Commun, 2012, 3: 662[2012-02-07]. http://dx.doi.org/10.1038/ncomms1648. DOI:10.1038/ncomms1648.
14. Nixon RA, Yang DS. Autophagy failure in Alzheimer’s disease--locating the primary defect[J]. Neurobiol Dis, 2011, 43(1): 38-45. DOI:10.1016/j.nbd.2011.01.021.
15. Mouchiroud L, Houtkooper RH, Moullan N, et al. The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial UPR and Foxo signaling[J]. Cell, 2013, 154(2): 430-441. DOI:10.1016/j.cell.2013.06.016.
16. Cuervo AM, Bergamini E, Brunk UT, et al. Autophagy and aging: the importance of maintaining "clean" cells[J]. Autophagy, 2005, 1(3): 131-140.
17. Madeo F, Tavernarakis N, Kroemer G. Can autophagy promote longevity?[J]. Nat Cell Biol, 2010, 12(9): 842-846. DOI:10.1038/ncb0910-842.
18. Taneike M, Yamaguchi O, Nakai A, et al. Inhibition of autophagy in the heart induces age-related cardiomyopathy[J]. Autophagy, 2010, 6(5): 600-606. DOI:10.4161/auto.6.5.11947.
19. Vellai T. Autophagy genes and ageing[J]. Cell Death Differ, 2009, 16(1): 94-102. DOI:10.1038/cdd.2008.126.
20. Simonsen A, Cumming RC, Brech A, et al. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult drosophila[J]. Autophagy, 2008, 4(2): 176-184.
21. Pillai VB, Sundaresan NR, Gupta MP. Regulation of Akt signaling by sirtuins: its implication in cardiac hypertrophy and aging[J]. Circ Res, 2014, 114(2): 368-378. DOI:10.1161/circresaha.113.300536.
22. Jarrett SG, Boulton ME. Consequences of oxidative stress in age-related macular degeneration[J]. Mol Aspects Med, 2012, 33(4): 399-417. DOI:10.1016/j.mam.2012.03.009.
23. Sanchez-Fidalgo S, Villegas I, Sanchez-Hidalgo M, et al. Sirtuin modulators: mechanisms and potential clinical implications[J]. Curr Med Chem, 2012, 19(15): 2414-2441.
24. Shao J, Yang X, Liu T, et al. Autophagy induction by SIRT6 is involved in oxidative stress-induced neuronal damage[J]. Protein Cell, 2016, 7(4): 281-290. DOI:10.1007/s13238-016-0257-6.
25. Lerrer B, Cohen HY. The guardian: metabolic and tumour-suppressive effects of SIRT6[J]. EMBO J, 2013, 32(1): 7-8. DOI:10.1038/emboj.2012.332.
26. Lyssiotis CA, Cantley LC. SIRT6 puts cancer metabolism in the driver’s seat[J]. Cell, 2012, 151(6): 1155-1156. DOI:10.1016/j.cell.2012.11.020.
27. Cardus A, Uryga AK, Walters G, et al. SIRT6 protects human endothelial cells from DNA damage, telomere dysfunction, and senescence[J]. Cardiovasc Res, 2013, 97(3): 571-579. DOI:10.1093/cvr/cvs352.
28. Mostoslavsky R, Chua KF, Lombard DB, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6[J]. Cell, 2006, 124(2): 315-329. DOI:10.1016/j.cell.2005.11.044.
29. Berryman DE, Christiansen JS, Johannsson G, et al. Role of the GH/IGF-1 axis in lifespan and healthspan: lessons from animal models[J]. Growth Horm IGF Res, 2008, 18(6): 455-471. DOI:10.1016/j.ghir.2008.05.005.
30. Zhong L, D’urso A, Toiber D, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha[J]. Cell, 2010, 140(2): 280-293. DOI:10.1016/j.cell.2009.12.041.
31. Silberman DM, Ross K, Sande PH. SIRT6 is required for normal retinal function[J/OL]. PLoS One, 2014, 9(6): 98831[2014-06-04]. http://dx.plos.org/10.1371/journal.pone.0098831. DOI: 10.1371/journal.pone.0098831.
32. Sundaresan NR, Vasudevan P, Zhong L, et al. The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun[J]. Nat Med, 2012, 18(11): 1643-1650. DOI:10.1038/nm.2961.
33. Xiao C, Wang RH, Lahusen TJ, et al. Progression of chronic liver inflammation and fibrosis driven by activation of c-JUN signaling in Sirt6 mutant mice[J]. J Biol Chem, 2012, 287(50): 41903-41913. DOI:10.1074/jbc.M112.415182.
34. Rodriguez-Muela N, Koga H, Garcia-Ledo L, et al. Balance between autophagic pathways preserves retinal homeostasis[J]. Aging cell, 2013, 12(3): 478-488. DOI:10.1111/acel.12072.
35. Krohne TU, Stratmann NK, Kopitz J, et al. Effects of lipid peroxidation products on lipofuscinogenesis and autophagy in human retinal pigment epithelial cells[J]. Exp Eye Res, 2010, 90(3): 465-471. DOI:10.1016/j.exer.2009.12.011.
36. Feng Y, Liang J, Zhai Y, et al. Autophagy activated by SIRT6 regulates Abeta induced inflammatory response in RPEs[J]. Biochem Biophys Res Commun, 2018, 496(4): 1148-1154. DOI:10.1016/j.bbrc.2018.01.159.
37. Salminen A, Kaarniranta K, Kauppinen A. Inflammaging: disturbed interplay between autophagy and inflammasomes[J]. Aging, 2012, 4(3): 166-175.
38. Wang L, Ebrahimi KB, Chyn M, et al. Biology of p62/sequestosome-1 in age-related macular degeneration (AMD)[J]. Adv Exp Med Biol, 2016, 854: 17-22. DOI:10.1007/978-3-319-17121-0_3.
39. Wang Y, Hanus JW, Abu-Asab MS, et al. NLRP3 upregulation in retinal pigment epithelium in age-related macular degeneration[J/OL]. Int J Mol Sci, 2016, 17(1): 73[2016-01-08]. http://www.mdpi.com/resolver?pii=ijms17010073. DOI:10.3390/ijms17010073.
40. Tanaka Y, Kume S, Kitada M, et al. Autophagy as a therapeutic target in diabetic nephropathy[J/OL]. Exp Diabetes Res, 2012, 2012: 628978[2011-10-19]. https://dx.doi.org/10.1155/2012/628978. DOI:10.1155/2012/628978.
41. Wang W, Wang Q, Wan D, et al. Histone HIST1H1C/H1.2 regulates autophagy in the development of diabetic retinopathy[J]. Autophagy, 2017, 13(5): 941-954. DOI:10.1080/15548627.2017.1293768.
42. Mao J, Xia Q, Liu C, et al. A critical role of Hrd1 in the regulation of optineurin degradation and aggresome formation[J]. Hum Mol Genet, 2017, 26(10): 1877-1889. DOI:10.1093/hmg/ddx096.
43. Takasaka N, Araya J, Hara H, et al. Autophagy induction by SIRT6 through attenuation of insulin-like growth factor signaling is involved in the regulation of human bronchial epithelial cell senescence[J]. J Immunol, 2014, 192(3): 958-968. DOI:10.4049/jimmunol.1302341.

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