본문 바로가기
KERD
논문KCI 등재

Tetrahydrobiopterin metabolism attenuates ROS generation and radiosensitivity through LDHA S-nitrosylation: novel insight into radiogenic lung injury

2

조회

0

다운로드

0

인용

0

참고문헌

주제분류생화학

초록

Genotoxic therapy triggers reactive oxygen species (ROS) production and oxidative tissue injury. S-nitrosylation is a selective and reversible posttranslational modification of protein thiols by nitric oxide (NO), and 5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis. However, the mechanism by which BH4 affects protein S-nitrosylation and ROS generation has not been determined. Here, we showed that ionizing radiation disrupted the structural integrity of BH4 and downregulated GTP cyclohydrolase I (GCH1), which is the rate-limiting enzyme in BH4 biosynthesis, resulting in deficiency in overall protein S-nitrosylation. GCH1-mediated BH4 synthesis significantly reduced radiation-induced ROS production and fueled the global protein S-nitrosylation that was disrupted by radiation. Likewise, GCH1 overexpression or the administration of exogenous BH4 protected against radiation-induced oxidative injury in vitro and in vivo. Conditional pulmonary Gch1 knockout in mice (Gch1fl/fl; Sftpa1-Cre+/− mice) aggravated lung injury following irradiation, whereas Gch1 knock-in mice (Gch1lsl/lsl; Sftpa1-Cre+/− mice) exhibited attenuated radiation-induced pulmonary toxicity. Mechanistically, lactate dehydrogenase (LDHA) mediated ROS generation downstream of the BH4/NO axis, as determined by iodoacetyl tandem mass tag (iodoTMT)-based protein quantification. Notably, S-nitrosylation of LDHA at Cys163 and Cys293 was regulated by BH4 availability and could restrict ROS generation. The loss of S-nitrosylation in LDHA after irradiation increased radiosensitivity. Overall, the results of the present study showed that GCH1-mediated BH4 biosynthesis played a key role in the ROS cascade and radiosensitivity through LDHA S-nitrosylation, identifying novel therapeutic strategies for the treatment of radiation-induced lung injury.

Abstract

Genotoxic therapy triggers reactive oxygen species (ROS) production and oxidative tissue injury. S-nitrosylation is a selective and reversible posttranslational modification of protein thiols by nitric oxide (NO), and 5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis. However, the mechanism by which BH4 affects protein S-nitrosylation and ROS generation has not been determined. Here, we showed that ionizing radiation disrupted the structural integrity of BH4 and downregulated GTP cyclohydrolase I (GCH1), which is the rate-limiting enzyme in BH4 biosynthesis, resulting in deficiency in overall protein S-nitrosylation. GCH1-mediated BH4 synthesis significantly reduced radiation-induced ROS production and fueled the global protein S-nitrosylation that was disrupted by radiation. Likewise, GCH1 overexpression or the administration of exogenous BH4 protected against radiation-induced oxidative injury in vitro and in vivo. Conditional pulmonary Gch1 knockout in mice (Gch1fl/fl; Sftpa1-Cre+/− mice) aggravated lung injury following irradiation, whereas Gch1 knock-in mice (Gch1lsl/lsl; Sftpa1-Cre+/− mice) exhibited attenuated radiation-induced pulmonary toxicity. Mechanistically, lactate dehydrogenase (LDHA) mediated ROS generation downstream of the BH4/NO axis, as determined by iodoacetyl tandem mass tag (iodoTMT)-based protein quantification. Notably, S-nitrosylation of LDHA at Cys163 and Cys293 was regulated by BH4 availability and could restrict ROS generation. The loss of S-nitrosylation in LDHA after irradiation increased radiosensitivity. Overall, the results of the present study showed that GCH1-mediated BH4 biosynthesis played a key role in the ROS cascade and radiosensitivity through LDHA S-nitrosylation, identifying novel therapeutic strategies for the treatment of radiation-induced lung injury.

참고문헌 (69)

  1. Wang, K., "Radiation therapy-associated toxicity : Etiology, man agement, and prevention", CA Cancer J. Clin, 71, pp.437~454 (2021)
  2. Yahyapour, R., "Reduction-oxidation(redox)system in radiation-induced normal tissue injury : molecular mechanisms and implications in radiation ther apeutics", Clin. Transl. Oncol, 20, pp.975~988 (2018)
  3. Pohjoismäki, J. L. O., "Adaptive and pathological outcomes of radiation stress-induced redox signaling", Antioxid. Redox Signal, 37, pp.336~348 (2022)
  4. Farhood, B., "Intercellular communications-redox interactions in radiation toxicity; potential targets for radiation mitigation", J. Cell Commun. Signal, 13, pp.3~16 (2019)
  5. Frey, B., "Modulation of inflammation by low and high doses of ionizing radiation : Implications for benign and malign diseases", Cancer Lett, 368, pp.230~237 (2015)
  6. Zhao, W., "Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications", Curr. Med. Chem, 16, pp.130~143 (2009)
  7. Robbins, M. E. C., "Chronic oxidative stress and radiation-induced late normal tissue injury: a review", Int. J. Radiat. Biol, 80, pp.251~259 (2004)
  8. Thöny, B., "Tetrahydrobiopterin biosynthesis, regeneration and functions", Biochem. J, 347, pp.1~16 (2000)
  9. Chuaiphichai, S., "Cell-autonomous role of endothelial GTP cyclohydrolase 1and tetrahydrobiopterin in blood pressure regulation", Hypertension, 64, pp.530~540 (2014)
  10. Berbée, M., "Novel strategies to ameliorate radiation injury: a possible role for tetrahydrobiopterin", Curr. Drug Targets, 11, pp.1366~1374 (2010)
  11. Crabtree, M. J., "Ratio of 5,6,7,8tetrahydrobiopterin to 7,8-dihydrobiopterin in endothelial cells determines glucose-elicited changes in NO vs. superoxide production by eNOS", Am. J. Physiol. Heart Circ. Physiol, 294, pp.H1530~H1540 (2008)
  12. Kraft, V. A. N., "GTP cyclohydrolase 1", tetrahydrobiopterin counteract fer roptosis through lipid remodeling, 2020, pp.6, 41~53
  13. Xue, J., "The Nrf2", GCH1, J. Investig. Dermatol, pp.2017, 137[DOI]
  14. Yan, T., "Ionizing radiation induces BH deficiency by downregulating GTP cyclohydrolase 1, a novel target for preventing and treating radiation enteritis", Biochem. Pharmacol, 180, pp.114102~ (2020)
  15. Feng, Y., "The critical role of tetrahydrobiopterin(BH4)metabolism in modulating radiosensitivity : BH4", NOS axis as an angel or a devil, 2021, pp.11, 720632~
  16. Wang, J., "Significance of endothelial dysfunction in the pathogenesis of early and delayed radiation enteropathy", World J. Gastroenterol, 13, pp.3047~3055 (2007)
  17. Förstermann, U., "Nitric oxide synthases : regulation and function", Eur. Heart J, 33, pp.829~837 (2012)
  18. Vimalraj, S., "Nitric oxide regulates intussusceptive-like angiogenesis in wound repair in chicken embryo and transgenic zebrafish models", Nitric Oxide : Biol. Chem, 82, pp.48~58 (2019)
  19. Hara, M. R., "S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding", Nat. Cell Biol, 7, pp.665~674 (2005)
  20. Hess, D. T., "Protein S nitrosylation : purview and parameters", Nat. Rev. Mol. Cell Biol, 6, pp.150~166 (2005)
  21. Stomberski, C. T., "Protein S-nitrosylation : determinants of specificity and enzymatic regulation of S-nitrosothiol-based signaling", Antioxid. Redox Signal, 30, pp.1331~1351 (2019)
  22. Marshall, H. E., "Nitrosation and oxidation in the regulation of gene expression", FASEB J, 14, pp.1889~1900 (2000)
  23. Jaiswal, M., "Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism", Cancer Res, 60, pp.184~190 (2000)
  24. Zhang, S., "REV3L 3’UTR 460 T>C polymorphism in microRNA target sites contributes to lung cancer susceptibility", Oncogene, 32, pp.242~250 (2013)
  25. Nie, J. -H., "Analysis of the miRNA-mRNA networks in malignant transforma tion BEAS-2B cells induced by alpha-particles", J. Toxicol. Environ. Health. A, 79, pp.427~435 (2016)
  26. Steber, C. R., "Five-versus ten-fraction regimens of stereotactic body radiation therapy for primary and metastatic NSCLC", Clin. Lung Cancer, 22, pp.e122~e131 (2021)
  27. Xie, L., "Integrating microRNA and mRNA expression profiles in response to radiation-induced injury in rat lung", Radiat. Oncol, 9, pp.111~ (2014)
  28. Amini, A., "Stereotactic body radiation therapy(SBRT)for lung cancer patients previously treated with con ventional radiotherapy : a review", Radiat. Oncol, 9, pp.210~ (2014)
  29. van Baardwijk, A., "Is high-dose stereotactic body radiotherapy(SBRT)for stage I non-small cell lung cancer(NSCLC)overkill? A systematic review", Radiother. Oncol, 105, pp.145~149 (2012)
  30. Li, L., "GTP cyclohydrolase I phosphorylation and interaction with GTP cyclohydrolase feedback regulatory protein provide novel regulation of endo thelial tetrahydrobiopterin and nitric oxide", Circ. Res, 106, pp.328~336 (2010)
  31. Naylor, A. M., "The tetrahydrobiopterin pathway and pain", Curr. Opin. Investig. Drugs, 11, pp.19~30 (2010)
  32. Buglak, A. A., "Photooxidation of tetrahydrobiopterin under UV irradiation : possible pathways and mechanisms", Photochem. Photobiol, 90, pp.1017~1026 (2014)
  33. Hasegawa, H., "Delivery of exogenous tetrahydrobiopterin(BH4)to cells of target organs : role of salvage pathway and uptake of its precursor in effective elevation of tissue BH4", Mol. Genet. Metab, 86, pp.S2~S10 (2005)
  34. Yi, M., "Irradiated human umbilical vein endothelial cells undergo endothelial-mesenchymal transition via the snail", miR-199a-5p axis to promote the differentiation of fibroblasts into myofibroblasts, 2018, pp.2018, 4135806~
  35. Wang, W., "Proteomic profiling of radiation-induced skin fibrosis in rats : targeting the ubiquitin-proteasome system", Int. J. Radiat. Oncol. Biol. Phys, 95, pp.751~760 (2016)
  36. Kopp, J., "N-acetyl-L-cysteine abrogates fibrogenic properties of fibroblasts isolated from Dupuytren’s disease by blunting TGF-beta signalling", J. Cell. Mol. Med, 10, pp.157~165 (2006)
  37. Saura, M., "Nitric oxide regulates transforming growth factor-beta signaling in endothelial cells", Circ. Res, 97, pp.1115~1123 (2005)
  38. Macias, M. J., "Structural determinants of Smad function in TGF-β signaling", Trends Biochem. Sci, 40, pp.296~308 (2015)
  39. Douglas, G., "A requirement for Gch1 and tetrahydrobiopterin in embryonic development", Dev. Biol, 399, pp.129~138 (2015)
  40. Zhang, S., "Protein and miRNA profiling of radiation-induced skin injury in rats : the protective role of peroxiredoxin-6 against ionizing radiation", Free Radic. Biol. Med, 69, pp.96~107 (2014)
  41. Shi, X., "Post-translational S-nitrosylation of proteins in regulating cardiac oxidative stress", Antioxidants, 9, pp.1051~ (2020)
  42. Liu, Y., "Nuclear lactate dehydrogenase A senses ROS to produce α-hydro xybutyrate for HPV-induced cervical tumor growth", Nat. Commun, 9, pp.4429~ (2018)
  43. Arra, M., "LDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis", Nat. Commun, 11, pp.3427~ (2020)
  44. Li, R., "Identification of total reversible cysteine oxidation in an atherosclerosis model using a modified biotin switch assay", J. Proteome Res, 14, pp.2026~2035 (2015)
  45. Liu, Q., "GSNOR facilitates antiviral innate immunity by restricting TBK1cysteine S-nitrosation", Redox Biol, 47, pp.102172~ (2021)
  46. Petrat, F., "Initiation of a superoxide dependent chain oxidation of lactate dehydrogenase-bound NADH by oxidants of low and high reactivity", Free Radic. Res, 39, pp.1043~1057 (2005)
  47. Pohl, C., "Cellular quality control by the ubiquitin-proteasome system and autophagy", Science, 366, pp.818~822 (2019)
  48. Medicherla, B., "Heat shock and oxygen radicals stimulate ubiquitin-dependent degradation mainly of newly synthesized proteins", J. Cell Biol, 182, pp.663~673 (2008)
  49. Sharma, S., "Preserving mitochondrial function prevents the proteasomal degradation of GTP cyclohydrolase I", Free Radic. Biol. Med, 53, pp.216~229 (2012)
  50. McBride, W. H., "The role of the ubiquitin", proteasome system in cellular responses to radiation, 2003, pp.22, 5755~5773
  51. Jing, X., "Caffeine ameliorates hyperoxia-induced lung injury by protecting GCH1 function in neonatal rat pups", Pediatr. Res, 82, pp.483~489 (2017)
  52. Giuranno, L., "Radiation-Induced Lung Injury(RILI)", Front. Oncol, 9, pp.877~ (2019)
  53. Mahmood, J., "Mitigation of lung injury after accidental exposure to radiation", Radiat. Res, 176, pp.770~780 (2011)
  54. Hanania, A. N., "Radiation-induced lung injury: assessment and management", Chest, 156, pp.150~162 (2019)
  55. Svendsen, E. R., "137Cesium exposure and spirometry measures in Ukrainian children affected by the Chernobyl nuclear incident", Environ. Health Perspect, 118, pp.720~725 (2010)
  56. Du, J., "Identification and functional characterization of phosphorylation sites on GTP cyclohydrolase I", Arterioscler. Thromb. Vasc. Biol, 29, pp.2161~2168 (2009)
  57. Bendall, J. K., "Tetra hydrobiopterin in cardiovascular health and disease", Antioxid. Redox Signal, 20, pp.3040~3077 (2014)
  58. Whitsett, J., "Human endothelial dihydrofolate reductase low activity limits vascular tetrahydrobiopterin recycling", Free Radic. Biol. Med, 63, pp.143~150 (2013)
  59. Dumitrescu, C., "Myocardial ischemia results in tetrahydrobiopterin(BH4)oxidation with impaired endothelial function ameliorated by BH4", Proc. Natl Acad. Sci. USA, 104, pp.15081~15086 (2007)
  60. Xie, L., "Liposomal tetra hydrobiopterin preserves eNOS coupling in the post-ischemic heart conferring in vivo cardioprotection", J. Mol. Cell. Cardiol, 86, pp.14~22 (2015)
  61. Hofmeister, L. H., "Phage-display-guided nanocarrier targeting to ather oprone vasculature", ACS Nano, 9, pp.4435~4446 (2015)
  62. Kourosh-Arami, M., "Neurophysiologic implications of neuronal nitric oxide synthase", Rev. Neurosci, 31, pp.617~636 (2020)
  63. Foster, M. W., "S-nitrosylation in health and disease", Trends Mol. Med, 9, pp.160~168 (2003)
  64. Cho, D. -H., "S-nitrosylation of Drp1 mediates beta-amyloid-related mito chondrial fission and neuronal injury", Science, 324, pp.102~105 (2009)
  65. Thabet, N. M., "Modulation of the nitric oxide", BH4 pathway protects against irradiation-induced neuronal damage, 2021, pp.46, 1641~1658
  66. Augoff, K., "Lactate dehydrogenase 5 : an old friend and a new hope in the war on cancer", Cancer Lett, 358, pp.1~7 (2015)
  67. Judge, J. L., "Prevention and treatment of bleomycin-induced pulmonary f ibrosis with the lactate dehydrogenase inhibitor gossypol", PLoS ONE, 13, pp.e0197936~ (2018)
  68. Judge, J. L., "The lactate dehydrogenase inhibitor gossypol inhibits radiation induced pulmonary fibrosis", Radiat. Res, 188, pp.35~43 (2017)
  69. Zhang, D., "Metabolic regulation of gene expression by histone lactylation", Nature, 574, pp.575~580 (2019)

관련 논문AI추천

이 간행물의 다른 논문 (218건)