microRNA Biogenesis during Cellular Senesence Induced by Chronic Stress of the Endoplasmic Reticulum

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

MicroRNAs are small non-coding regulatory RNAs about 22 nt long, post-transcriptional and transcriptional regulators of gene expression that stabilize the cellular phenotype and play an important role in differentiation, development, and apoptosis. MicroRNA biogenesis includes several precisely controlled post-transcriptional stages of processing and transport, including cytoplasmic cleavage of pre-miRNA by type III ribonuclease DICER with the formation of a mature duplex included in the RISC complex. The role of miRNA and its biogenesis are not well understood in such an important process as cellular stress. Cellular stress is a non-specific cellular response to non-physiological stimuli that can switch a cell to death or cellular senescence. The global decrease in microRNA levels is a key feature of cancer cells and an important reason for the formation of a malignant phenotype. In this work, using flow cytometry and high-throughput analysis of gene expression, we showed that chronic endoplasmic reticulum (ER) stress, one of the types of cellular stress associated with impaired protein folding in the ER, leads to the formation of a cellular aging phenotype in fibroblast-like FRSN cells. Despite the fact that acute ER stress can reduce miRNA biogenesis, chronic stress does not lead to a significant drop in global miRNA expression and is accompanied by only a slight decrease in DICER1 mRNA expression. Under chronic ER stress, we found an increase in cell population heterogeneity in terms of lysosomal beta-galactosidase activity, which does not exclude induced or initial cell heterogeneity and in terms of expression of microRNA biogenesis pathway components.

About the authors

D. M. Zaichenko

Institute of General Pathology and Pathophysiology

Email: bioinf@mail.ru
Russia, 125315, Moscow

A. A. Mikryukova

Institute of General Pathology and Pathophysiology

Email: bioinf@mail.ru
Russia, 125315, Moscow

I. R. Astafeva

Institute of General Pathology and Pathophysiology

Email: bioinf@mail.ru
Russia, 125315, Moscow

S. G. Malakho

Botkin City Clinical Hospital of the Moscow City Health Department

Email: bioinf@mail.ru
Russia, 125284, Moscow

A. A. Kubatiev

Institute of General Pathology and Pathophysiology; Russian Medical Academy of Continuing Professional Education (RMANPO), Ministry of Health of the Russian Federation

Email: bioinf@mail.ru
Russia, 125315, Moscow; Russia, 125993, Moscow

A. A. Moskovtsev

Institute of General Pathology and Pathophysiology; Russian Medical Academy of Continuing Professional Education (RMANPO), Ministry of Health of the Russian Federation

Author for correspondence.
Email: bioinf@mail.ru
Russia, 125315, Moscow; Russia, 125993, Moscow

References

  1. Kozutsumi Y., Segal M., Normington K., Gething M.J., Sambrook J. (1988) The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature. 332, 462–464. https://doi.org/10.1038/332462A0
  2. Schröder M., Kaufman R.J. (2005) The mammalian unfolded protein response. Annu. Rev. Biochem. 74, 739‒789. https://doi.org/10.1146/annurev.biochem.73.011303.074134
  3. Меситов М.В., Московцев А.А., Кубатеев А.А. (2013) Молекулярная логика сигнальных путей при стрессе эндоплазматического ретикулума: система UPR (Unfolded Protein Response). Патологическая физиология и экспериментальная терапия. 57(4), 97–108. https://pubmed.ncbi.nlm.nih.gov/24640782/
  4. Acosta-Alvear D., Karagöz G.E., Fröhlich F., Li H., Walther T.C., Walter P. (2018) The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1. Elife. 7, e43036. https://doi.org/10.7554/eLife.43036
  5. Korennykh A., Walter P. (2012) Structural basis of the unfolded protein response. Annu. Rev. Cell Develop. Biol. 28, 251–277. https://doi.org/10.1146/annurev-cellbio-101011-155826
  6. Московцев А.А., Клементьева Т.С., Зайченко Д.М., Колесов Д.В., Соколовская А.А., Кубатиев А.А. (2018) Проадаптивная и проапоптотическая активности стресс-активируемой рибонуклеазы IRE1: разделение на временнóй шкале клеточного стресса. Патологическая физиология и экспериментальная терапия. 62, 21–27. https://doi.org/10.25557/0031-2991.2018.04.21-27
  7. Mesitov M.V., Soldatov R.A., Zaichenko D.M., Malakho S.G., Klementyeva T.S., Sokolovskaya A.A., Kubatiev A.A., Mironov A.A., Moskovtsev A.A. (2017) Differential processing of small RNAs during endoplasmic reticulum stress. Sci. Rep. 7, 46080. https://doi.org/10.1038/srep46080
  8. Bartel D.P. (2009) MicroRNAs: target recognition and regulatory functions. Cell. 136, 215–233. https://doi.org/10.1016/j.cell.2009.01.002
  9. Lee R.C., Feinbaum R.L., Ambros V. (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 75, 843–854. https://doi.org/10.1016/0092-8674(93)90529-Y
  10. Kim D.H., Sætrom P., Snøve O., Rossi J.J. (2008) MicroRNA-directed transcriptional gene silencing in mammalian cells. Proc. Natl. Acad. Sci. USA. 105, 16230–16235. https://doi.org/10.1073/PNAS.0808830105
  11. Kozomara A., Griffiths-Jones S. (2014) miRBase: annotating high confidence microRNAs using deep sequencing data. Nucl. Acids Res. 42, 68–73. https://doi.org/10.1093/nar/gkt1181
  12. Kim V.N., Han J., Siomi M.C. (2009) Biogenesis of small RNAs in animals. Nat. Rev. Mol. Cell Biol. 10, 126–139. https://doi.org/10.1038/nrm2632
  13. Bartel D.P. (2018) Metazoan microRNAs. Cell. 173, 20–51. https://doi.org/10.1016/j.cell.2018.03.006
  14. Fabian M.R., Sonenberg N., Filipowicz W. (2010) Regulation of mRNA translation and stability by microRNAs. Annu. Rev. Biochem. 79, 351–379. https://doi.org/10.1146/ANNUREV-BIOCHEM-060308-103103
  15. Wienholds E., Koudijs M.J., van Eeden F.J., Cuppen E., Plasterk R.H. (2003) The microRNA-producing enzyme Dicer1 is essential for zebrafish development. Nat. Genet. 35, 217–218. https://doi.org/10.1038/NG1251
  16. Bernstein E., Kim S.Y., Carmell M.A., Murchison E.P., Alcorn H., Li M.Z., Mills A.A., Elledge S.J., Anderson K.V., Hannon G.J. (2003) Dicer is essential for mouse development. Nat. Genet. 35, 215–217. https://doi.org/10.1038/NG1253
  17. Martello G., Rosato A., Ferrari F., Manfrin A., Cordenonsi M., Dupont S., Enzo E., Guzzardo V., Rondina M., Spruce T., Parenti A.R., Daidone M.G., Bicciato S., Piccolo S. (2010) A microRNA targeting dicer for metastasis control. Cell. 141, 1195–1207. https://doi.org/10.1016/J.CELL.2010.05.017
  18. Pampalakis G., Diamandis E.P., Katsaros D., Sotiropoulou G. (2010) Down-regulation of dicer expression in ovarian cancer tissues. Clin. Biochemistry. 43, 324–327. https://doi.org/10.1016/J.CLINBIOCHEM.2009.09.014
  19. Kaneko H., Dridi S., Tarallo V., Gelfand B.D., Fowler B.J., Cho W.G., Kleinman M.E., Ponicsan S.L., Hauswirth W.W., Chiodo V.A., Karikó K., Yoo J.W., Lee D.K., Hadziahmetovic M., Song Y., Misra S., Chaudhuri G., Buaas F.W., Braun R.E., Hinton D.R., Zhang Q., Grossniklaus H.E., Provis J.M., Madigan M.C., Milam A.H., Justice N.L., Albuquerque R.J.C., Blandford A.D., Bogdanovich S., Hirano Y., Witta J., Fuchs E., Littman D.R., Ambati B.K., Rudin C.M., Chong M.M., Provost P., Kugel J.F., Goodrich J.A., Dunaief J.L., Baffi J.Z., Ambati J. (2011) DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature. 471, 325–332. https://doi.org/10.1038/NATURE09830
  20. Kumar M.S., Lu J., Mercer K.L., Golub T.R., Jacks T. (2007) Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat. Genet. 39, 673–677. https://doi.org/10.1038/ng2003
  21. Toussaint O., Medrano E.E., von Zglinicki T. (2000) Cellular and molecular mechanisms of stress-induced premature senescence (SIPS) of human diploid fibroblasts and melanocytes. Exp. Gerontology. 35, 927–945. https://doi.org/10.1016/S0531-5565(00)00180-7
  22. Childs B.G., Durik M., Baker D.J., Van Deursen J.M. (2015) Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat. Medicine. 21(12), 1424–1435. https://doi.org/10.1038/nm.4000
  23. Narita M., Nũnez S., Heard E., Narita M., Lin A.W., Hearn S.A., Spector D.L., Hannon G. J., Lowe S.W. (2003) Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 113, 703–716. https://doi.org/10.1016/S0092-8674(03)00401-X
  24. Hayflick L. (1965) The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614–636. https://doi.org/10.1016/0014-4827(65)90211-9
  25. Lee S., Schmitt C.A. (2019) The dynamic nature of senescence in cancer. Nat. Cell. Biol. 21, 94–101. https://doi.org/10.1038/s41556-018-0249-2
  26. Seshadri T., Campisi J. (1990) Repression of c-fos transcription and an altered genetic program in senescent human fibroblasts. Science. 247, 205–209. https://doi.org/10.1126/SCIENCE.2104680
  27. Beauséjour C.M., Krtolica A., Galimi F., Narita M., Lowe S.W., Yaswen P., Campisi J. (2003) Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 22, 4212–4222. https://doi.org/10.1093/EMBOJ/CDG417
  28. Milanovic M., Fan D.N.Y., Belenki D., Däbritz J.H.M., Zhao Z., Yu Y., Dörr J.R., Dimitrova L., Lenze D., Monteiro Barbosa I.A., Mendoza-Parra M.A., Kanashova T., Metzner M., Pardon K., Reimann M., Trumpp A., Dörken B., Zuber J., Gronemeyer H., Hummel M., Dittmar G., Lee S., Schmitt C.A. (2018) Senescence-associated reprogramming promotes cancer stemness. Nature. 553, 96–100. https://doi.org/10.1038/nature25167
  29. Pluquet O., Pourtier A., Abbadie C. (2015) The unfolded protein response and cellular senescence. A review in the theme: cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. Am. J. Physiol. Cell Physiol. 308, 415–425. https://doi.org/10.1152/ajpcell.00334.2014
  30. Subramanian A., Tamayo P., Mootha V.K., Mukherjee S., Ebert B.L., Gillette M.A., Paulovich A., Pomeroy S.L., Golub T.R., Lander E.S., Mesirov J.P. (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550. https://doi.org/10.1073/pnas.0506580102
  31. Reich M., Liefeld T., Gould J., Lerner J., Tamayo P., Mesirov J.P. (2006) GenePattern 2.0. Nat. Genet. 38, 500–501. https://doi.org/10.1038/ng0506-500
  32. Кухарский М.С., Эверетт М.У., Лыткина О.А., Распопова М.А., Ковражкина Е.А., Овчинников Р.К., Антохин А.И., Московцев А.А. (2022) Нарушение белкового гомеостаза в клетке как основа патогенеза нейродегенеративных заболеваний. Молекуляр. биология. 56(6), 1044‒1056.
  33. Stein G.H., Drullinger L.F., Soulard A., Dulić V. (1999) Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol. Cell. Biol. 19, 2109–2117. https://doi.org/10.1128/MCB.19.3.2109
  34. Wang A.S., Dreesen O. (2018) Biomarkers of cellular senescence and skin aging. Front. Genet. 9, 247. https://doi.org/10.3389/fgene.2018.00247
  35. Childs B.G., Baker D.J., Kirkland J.L., Campisi J., Van Deursen J.M. (2014) Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep. 15, 1139–1153. https://doi.org/10.15252/embr.201439245
  36. González-Gualda E., Baker A.G., Fruk L., Muñoz-Espín D. (2021) A guide to assessing cellular senescence in vitro and in vivo. FEBS J. 288, 56–80. https://doi.org/10.1111/FEBS.15570
  37. Braakman I., Helenius J., Helenius A. (1992) Manipulating disulfide bond formation and protein folding in the endoplasmic reticulum. EMBO J. 11, 1717–1722. https://doi.org/10.1002/J.1460-2075.1992.TB05223.X
  38. Oslowski C.M., Urano F. (2011) Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Methods Enzymol. 490, 71. https://doi.org/10.1016/B978-0-12-385114-7.00004-0
  39. Tu B.P., Weissman J.S. (2004) Oxidative protein folding in eukaryotes: mechanisms and consequences. J. Cell. Biol. 164, 341–346. https://doi.org/10.1083/JCB.200311055
  40. Hwang C., Sinskey A.J., Lodish H.F. (1992) Oxidized redox state of glutathione in the endoplasmic reticulum. Science. 257, 1496–1502. https://doi.org/10.1126/SCIENCE.1523409
  41. Меситов М.В., Игнашкова Т.И., Мещерский М.Е., Акопов А.С., Соколовская А.А., Московцев А.А., Кубатиев А.А. (2012) Индукция стресса эндоплазматического ретикулума в условиях окислительно-восстановительного дисбаланса в клетках Т-лимфобластной лейкемии человека. Патологическая физиология и экспериментальная терапия, 56(3), 87‒93. https://pubmed.ncbi.nlm.nih.gov/23072118/.
  42. Held K.D., Sylvester F.C., Hopcia K.L., Biaglow J.E. (1996) Role of Fenton chemistry in thiol-induced toxicity and apoptosis. Radiation Res. 145, 542–553. https://doi.org/10.2307/3579272
  43. Masciarelli S., Sitia R. (2008) Building and operating an antibody factory: redox control during B to plasma cell terminal differentiation. Biochim. Biophys. Acta. 1783(4), 578‒588. https://doi.org/10.1016/J.BBAMCR.2008.01.003
  44. Anelli T., Bergamelli L., Margittai E., Rimessi A., Fagioli C., Malgaroli A., Pinton P., Ripamonti M., Rizzuto R., Sitia R. (2012) Ero1α regulates Ca2+ fluxes at the endoplasmic reticulum–mitochondria interface (MAM). Antioxid. Redox Signal. 16, 1077–1087. https://doi.org/10.1089/ARS.2011.4004
  45. Tavender T.J., Bulleid N.J. (2010) Peroxiredoxin IV protects cells from oxidative stress by removing H2O2 produced during disulphide formation. J. Cell Sci. 123, 2672–2679. https://doi.org/10.1242/JCS.067843
  46. Zito E., Melo E.P., Yang Y., Wahlander Å., Neubert T.A., Ron D. (2010) Oxidative protein folding by an endoplasmic reticulum-localized peroxiredoxin. Mol. Cell. 40, 787. https://doi.org/10.1016/J.MOLCEL.2010.11.010
  47. Cormenier J., Martin N., Deslé J., Salazar-Cardozo C., Pourtier A., Abbadie C., Pluquet O. (2018) The ATF6α arm of the unfolded protein response mediates replicative senescence in human fibroblasts through a COX2/prostaglandin E2 intracrine pathway. Mech. Ageing Dev. 170, 82–91. https://doi.org/10.1016/J.MAD.2017.08.003
  48. Wiesen J.L., Tomasi T.B. (2009) Dicer is regulated by cellular stresses and interferons. Mol. Immunol. 46, 1222. https://doi.org/10.1016/J.MOLIMM.2008.11.012
  49. Emde A., Hornstein E. (2014) miRNAs at the interface of cellular stress and disease. EMBO J. 33, 1428–1437. https://doi.org/10.15252/EMBJ.201488142
  50. Otsuka M., Jing Q., Georgel P., New L., Chen J., Mols J., Kang Y.J., Jiang Z., Du X., Cook R., Das S.C., Pattnaik A.K., Beutler B., Han J. (2007) Hypersusceptibility to vesicular stomatitis virus infection in Dicer1-deficient mice is due to impaired miR24 and miR93 expression. Immunity. 27, 123–134. https://doi.org/10.1016/J.IMMUNI.2007.05.014
  51. Müller S., Imler J.L. (2007) Dicing with viruses: micro-RNAs as antiviral factors. Immunity. 27, 1–3. https://doi.org/10.1016/J.IMMUNI.2007.07.003
  52. Pagliuso D.C., Bodas D.M., Pasquinelli A.E. (2021) Recovery from heat shock requires the microRNA pathway in Caenorhabditis elegans. PLoS Genet. 17, e1009734. https://doi.org/10.1371/JOURNAL.PGEN.1009734
  53. Mori M.A., Raghavan P., Thomou T., Boucher J., Robida-Stubbs S., MacOtela Y., Russell S.J., Kirkland J.L., Blackwell T.K., Kahn C.R. (2012) Role of microRNA processing in adipose tissue in stress defense and longevity. Cell Metabolism. 16, 336‒347. https://doi.org/10.1016/J.CMET.2012.07.017
  54. Turi Z., Lacey M., Mistrik M., Moudry P. (2019) Impaired ribosome biogenesis: mechanisms and relevance to cancer and aging. Aging (Albany NY). 11, 2512. https://doi.org/10.18632/AGING.101922

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2.

Download (292KB)
Indexing metadata
3.

Download (41KB)
Indexing metadata
4.

Download (592KB)
Indexing metadata

Copyright (c) 2023 Д.М. Зайченко, А.А. Микрюкова, Я.Р. Астафьева, С.Г. Малахо, А.А. Кубатиев, А.А. Московцев