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O-GlcNAc transferase regulates intervertebral disc degeneration by targeting FAM134B-mediated ER-phagy

Yang Cao|Zhang Teng|Ke Wencan|Liao Zhiwei|Liang Huaizhen|Wang Bingjin|Luo Rongjin|Li Gaocai|Zhang Weifei|Lu Saideng|Cheung Jason Pui Yin|Tu Ji|Liu Hui|Song Yu
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2022.12|Experimental and Molecular Medicine|제54권 |pp. 1-14|DOI 10.1038/s12276-022-00844-7

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초록

Both O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) and endoplasmic reticulum-phagy (ER-phagy) are well-characterized conserved adaptive regulatory mechanisms that maintain cellular homeostasis and function in response to various stress conditions. Abnormalities in O-GlcNAcylation and ER-phagy have been documented in a wide variety of human pathologies. However, whether O-GlcNAcylation or ER-phagy is involved in the pathogenesis of intervertebral disc degeneration (IDD) is largely unknown. In this study, we investigated the function of O-GlcNAcylation and ER-phagy and the related underlying mechanisms in IDD. We found that the expression profiles of O-GlcNAcylation and O-GlcNAc transferase (OGT) were notably increased in degenerated NP tissues and nutrient-deprived nucleus pulposus (NP) cells. By modulating the O-GlcNAc level through genetic manipulation and specific pharmacological intervention, we revealed that increasing O-GlcNAcylation abundance substantially enhanced cell function and facilitated cell survival under nutrient deprivation (ND) conditions. Moreover, FAM134B-mediated ER-phagy activation was regulated by O-GlcNAcylation, and suppression of ER-phagy by FAM134B knockdown considerably counteracted the protective effects of amplified O-GlcNAcylation. Mechanistically, FAM134B was determined to be a potential target of OGT, and O-GlcNAcylation of FAM134B notably reduced FAM134B ubiquitination-mediated degradation. Correspondingly, the protection conferred by modulating O-GlcNAcylation homeostasis was verified in a rat IDD model. Our data demonstrated that OGT directly associates with and stabilizes FAM134B and subsequently enhances FAM134B-mediated ER-phagy to enhance the adaptive capability of cells in response to nutrient deficiency. These findings may provide a new option for O-GlcNAcylation-based therapeutics in IDD prevention.

Abstract

Both O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) and endoplasmic reticulum-phagy (ER-phagy) are well-characterized conserved adaptive regulatory mechanisms that maintain cellular homeostasis and function in response to various stress conditions. Abnormalities in O-GlcNAcylation and ER-phagy have been documented in a wide variety of human pathologies. However, whether O-GlcNAcylation or ER-phagy is involved in the pathogenesis of intervertebral disc degeneration (IDD) is largely unknown. In this study, we investigated the function of O-GlcNAcylation and ER-phagy and the related underlying mechanisms in IDD. We found that the expression profiles of O-GlcNAcylation and O-GlcNAc transferase (OGT) were notably increased in degenerated NP tissues and nutrient-deprived nucleus pulposus (NP) cells. By modulating the O-GlcNAc level through genetic manipulation and specific pharmacological intervention, we revealed that increasing O-GlcNAcylation abundance substantially enhanced cell function and facilitated cell survival under nutrient deprivation (ND) conditions. Moreover, FAM134B-mediated ER-phagy activation was regulated by O-GlcNAcylation, and suppression of ER-phagy by FAM134B knockdown considerably counteracted the protective effects of amplified O-GlcNAcylation. Mechanistically, FAM134B was determined to be a potential target of OGT, and O-GlcNAcylation of FAM134B notably reduced FAM134B ubiquitination-mediated degradation. Correspondingly, the protection conferred by modulating O-GlcNAcylation homeostasis was verified in a rat IDD model. Our data demonstrated that OGT directly associates with and stabilizes FAM134B and subsequently enhances FAM134B-mediated ER-phagy to enhance the adaptive capability of cells in response to nutrient deficiency. These findings may provide a new option for O-GlcNAcylation-based therapeutics in IDD prevention.

참고문헌 (56)

  1. Disease, G. B. D., "Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195countries, 1990-2016 : a systematic analysis for the Global Burden of Disease Study 2016", Lancet, 390, pp.1211~1259 (2017)
  2. Deyo, R. A., "Herniated lumbar intervertebral disk", N. Engl. J. Med, 374, pp.1763~1772 (2016)
  3. Mayer, J. E., "Genetic polymorphisms associated with intervertebral disc degeneration", Spine J, 13, pp.299~317 (2013)
  4. Vergroesen, P. P., "Mechanics and biology in intervertebral disc degeneration:a vicious circle", Osteoarthr. Cartil, 23, pp.1057~1070 (2015)
  5. Huang, Y. C., "Intervertebral disc regeneration : do nutrients lead the way?", Nat. Rev. Rheumatol, 10, pp.561~566 (2014)
  6. Zhao, C. Q., "The cell biology of intervertebral disc aging and degeneration", Ageing Res. Rev, 6, pp.247~261 (2007)
  7. Liao, Z., "Exosomes from mesenchymal stem cells modulate endoplasmic reticulum stress to protect against nucleus pulposus cell death and ameliorate intervertebral disc degeneration in vivo", Theranostics, 9, pp.4084~4100 (2019)
  8. Li, G., "Bone-derived mesenchymal stem cells alleviate compression-induced apoptosis of nucleus pulposus cells by N6 methyladenosine of autophagy", Cell Death Dis, 11, pp.103~ (2020)
  9. Luo, R., "Berberine ameliorates oxidative stress-induced apoptosis by modulating ER stress and autophagy in human nucleus pulposus cells", Life Sci, 228, pp.85~97 (2019)
  10. Grootjans, J., "The unfolded protein response in immunity and inflammation", Nat. Rev. Immunol, 16, pp.469~484 (2016)
  11. Chino, H., "ER-phagy : quality control and turnover of endoplasmic reticulum", Trends Cell Biol, 30, pp.384~398 (2020)
  12. Lipatova, Z., "A role for macro-ER-phagy in ER quality control", PLoS Genet, 11, pp.e1005390~ (2015)
  13. Khaminets, A., "Regulation of endoplasmic reticulum turnover by selective autophagy", Nature, 522, pp.354~358 (2015)
  14. Grumati, P., "Full length RTN3 regulates turnover of tubular endoplasmic reticulum via selective autophagy", Elife, 6, pp.e25555~ (2017)
  15. Smith, M. D., "CCPG1 is a non-canonical autophagy cargo receptor essential for ER-phagy and pancreatic ER proteostasis", Dev. Cell, 44, pp.217~232.e211 (2018)
  16. Chen, Q., "ATL3 is a tubular ER-phagy receptor for GABARAP-mediated selective autophagy", Curr. Biol, 29, pp.846~855.e846 (2019)
  17. Delorme-Axford, E., "TEX264 is a major receptor for mammalian reticulophagy", Autophagy, 15, pp.1677~1681 (2019)
  18. Fumagalli, F., "Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery", Nat. Cell. Biol, 18, pp.1173~1184 (2016)
  19. Hubner, C. A., "ER-phagy and human diseases", Cell Death Differ, 27, pp.833~842 (2020)
  20. Zhang, Z., "Repurposing brigatinib for the treatment of colorectal cancer based on inhibition of ER-phagy", Theranostics, 9, pp.4878~4892 (2019)
  21. Lennemann, N. J., "Dengue and Zika viruses subvert reticulophagy by NS2B3-mediated cleavage of FAM134B", Autophagy, 13, pp.322~332 (2017)
  22. Schjoldager, K. T., "Global view of human protein glycosylation pathways and functions", Nat. Rev. Mol. Cell Biol, 21, pp.729~749 (2020)
  23. Chatham, J. C., "Role of O-linked N-acetylglucosamine(OGlcNAc)protein modification in cellular(patho)physiology", Physiol. Rev, 101, pp.427~493 (2021)
  24. Yang, X., "Protein O-GlcNAcylation : emerging mechanisms and functions", Nat. Rev. Mol. Cell Biol, 18, pp.452~465 (2017)
  25. Banerjee, P. S., "Roles of O-GlcNAc in chronic diseases of aging", Mol. Asp. Med, 51, pp.1~15 (2016)
  26. Zhang, X., "GRASP55 senses glucose deprivation through O-GlcNAcylation to promote autophagosome-lysosome fusion", Dev. Cell, 45, pp.245~261.e246 (2018)
  27. Guo, B., "O-GlcNAc-modification of SNAP-29 regulates autophagosome maturation", Nat. Cell Biol, 16, pp.1215~1226 (2014)
  28. Wang, P., "Nutrient-driven O-GlcNAc cycling influences autophagic flux and neurodegenerative proteotoxicity", Autophagy, 9, pp.604~606 (2013)
  29. Georgios Nikolaou, "Detection of O-Linked-N-Acetylglucosamine Modification and Its Associated Enzymes in Human Degenerated Intervertebral Discs", Asian Spine Journal, 11(6), pp.863~869 (2017), 대한척추외과학회
  30. Pfirrmann, C. W. A., "Magnetic resonance classification of lumbar intervertebral disc degeneration", Spine, 26, pp.1873~1878 (2001)
  31. Song, Y., "Sirtuin 3-dependent mitochondrial redox homeostasis protects against AGEs-induced intervertebral disc degeneration", Redox Biol, 19, pp.339~353 (2018)
  32. Jianle Wang, "Small molecule natural compound agonist of SIRT3 as a therapeutic target for the treatment of intervertebral disc degeneration", Experimental and Molecular Medicine, 50, pp.1~14 (2018), 생화학분자생물학회
  33. Han, B., "A simple disc degeneration model induced by percutaneous needle puncture in the rat tail", Spine, 33, pp.1925~1934 (2008)
  34. Na, H. J., "Nutrient-driven O-GlcNAcylation controls DNA damage repair signaling and stem", progenitor cell homeostasis, 2020, pp.31, 107632~
  35. Park, J., "O-GlcNAcylation ameliorates the pathological manifestations of Alzheimer’s disease by inhibiting necroptosis", Sci. Adv, 7, pp.eabd3207~ (2021)
  36. Hwang, H., "Functional significance of O-GlcNAc modification in regulating neuronal properties", Pharmacol. Res, 129, pp.295~307 (2018)
  37. Yuzwa, S. A., "O-GlcNAc and neurodegeneration : biochemical mechanisms and potential roles in Alzheimer’s disease and beyond", Chem. Soc. Rev, 43, pp.6839~6858 (2014)
  38. Akan, I., "Nutrient-driven OGlcNAc in proteostasis and neurodegeneration", J. Neurochem, 144, pp.7~34 (2018)
  39. Wheatley, E. G., "Neuronal O-GlcNAcylation improves cognitive function in the aged mouse brain", Curr. Biol, 29, pp.3359~3369.e3354 (2019)
  40. Liu, H., "Proteasomal degradation of O-GlcNAc transferase elevates hypoxia-induced vascular endothelial inflammatory responsedagger", Cardiovasc. Res, 103, pp.131~139 (2014)
  41. Kronlage, M., "O-GlcNAcylation of histone deacetylase 4 protects the diabetic heart from failure", Circulation, 140, pp.580~594 (2019)
  42. Li, T., "O-GlcNAc transferase links glucose metabolism to MAVS-mediated antiviral innate immunity", Cell Host Microbe, 24, pp.791~803.e796 (2018)
  43. Settembre, C., "Defective collagen proteostasis and matrix formation in the pathogenesis of lysosomal storage disorders", Matrix Biol, 71-72, pp.283~293 (2018)
  44. Jiang, X., "FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER-phagy", EMBO J, 39, pp.e102608~ (2020)
  45. Islam, F., "RETREG1(FAM134B) : A new player in human diseases : 15 years after the discovery in cancer", J. Cell Physiol, 233, pp.4479~4489 (2018)
  46. Chiramel, A. I., "FAM134B, the selective autophagy receptor for endoplasmic reticulum turnover, inhibits replication of Ebola virus strains Makona and Mayinga", J. Infect. Dis, 214, pp.S319~S325 (2016)
  47. Liao, Y., "Excessive ER-phagy mediated by the autophagy receptor FAM134B results in ER stress, the unfolded protein response, and cell death in HeLa cells", J. Biol. Chem, 294, pp.20009~20023 (2019)
  48. Peng, Y., "Increased transport of acetyl-CoA into the endoplasmic reticulum causes a progeria-like phenotype", Aging Cell, 17, pp.e12820~ (2018)
  49. Yurube, T., "Notochordal cell disappearance and modes of apoptotic cell death in a rat tail static compression-induced disc degeneration model", Arthritis Res. Ther, 16, pp.R31~ (2014)
  50. Tsujimoto, R., "Involvement of autophagy in the maintenance of rat intervertebral disc homeostasis : an in-vitro and in-vivo RNA interference study of Atg5", Osteoarthr. Cartil, 30, pp.481~493 (2022)
  51. Yurube, T., "Involvement of autophagy in rat tail static compression-induced intervertebral disc degeneration and notochordal cell disappearance", Int. J. Mol. Sci, 22, pp.5648~ (2021)
  52. Pyo, K. E., "ULK1 O-GlcNAcylation is crucial for activating VPS34 via ATG14L during autophagy initiation", Cell Rep, 25, pp.2878~2890 (2018)
  53. Ruan, H. B., "Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation", Genes Dev, 31, pp.1655~1665 (2017)
  54. Park, S., "O-GlcNAc modification is essential for the regulation of autophagy in Drosophila melanogaster", Cell Mol. Life Sci, 72, pp.3173~3183 (2015)
  55. Rahman, M. A., "Modulation of O-GlcNAcylation regulates autophagy in cortical astrocytes", Oxid. Med. Cell. Longev, 2019, pp.6279313~ (2019)
  56. Yu, H., "O-GlcNAcylation is essential for autophagy in cardiomyocytes", Oxid. Med. Cell. Longev, 2020, pp.5602396~ (2020)

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