БИОХИМИЯ, 2020, том 85, вып. 2, с. 155–164

УДК 577.15

Гранзимы и митохондрии

Обзор

© 2020 Д.Б. Киселевский

Московский государственный университет им. М.В. Ломоносова, биологический факультет, 119991 Москва, Россия; электронная почта: dkiselevs@mail.ru

Поступила в редакцию 01.10.2019
После доработки 01.11.2019
Принята к публикации 04.11.2019

DOI: 10.31857/S0320972520020013

КЛЮЧЕВЫЕ СЛОВА: активные формы кислорода, апоптоз, гранзимы, митохондрии, программируемая клеточная смерть.

Аннотация

Цитотоксические Т-лимфоциты и естественные киллеры избавляют организм от зараженных клеток путем включения в них программы гибели (апоптоза). Это может происходить в результате высвобождения содержимого литических гранул клеток-киллеров, в которых локализованы порообразующие белки перфорины и протеолитические ферменты гранзимы, и их последующего проникновения в клетки-мишени. Гранзим B способен инициировать зависимый от митохондрий путь апоптоза несколькими способами: через 1) проапоптозный белок Bid, 2) белки Mcl-1 и Bim или 3) белок р53. В результате из митохондрий в цитоплазму выходит цитохром с, и образуются апоптосомы, обеспечивающие протеолитический каскад активации каспаз. Гранзимы М, H и F вызывают гибель клеток, которая сопровождается выходом цитохрома с из митохондрий. Гранзим А индуцирует образование активных форм кислорода (АФК), которые способствуют транслокации ассоциированного с эндоплазматическим ретикулумом комплекса SET в ядро клетки. В клеточном ядре гранзим А расщепляет SET; это активирует нуклеазы, которые осуществляют одноцепочечные разрывы ДНК. Гранзимы А и В проникают в митохондрии и разрезают субъединицы комплекса I дыхательной цепи. Одна из субъединиц комплекса I является мишенью также и для каспазы-3. Гранзим-зависимое повреждение комплекса I приводит к образованию АФК и гибели клеток.

Финансирование

Работа выполнена при финансовой поддержке научно-исследовательской работы (НИР) из средств федерального бюджета (регистрационный номер НИР в ЦИТИС: АААА-А16-116021660081-0).

Благодарности

Автор благодарен д.б.н. профессору В.Д. Самуилову за внимательное прочтение рукописи статьи и ценные замечания.

Конфликт интересов

Автор заявляет об отсутствии конфликта интересов.

Соблюдение этических норм

Настоящее исследование проводили без использования животных и без привлечения людей в качестве испытуемых.

Список литературы

1. Cullen, S.P., and Martin, S.J. (2008) Mechanisms of granule-dependent killing, Cell Death Differ., 15, 251–262, doi: 10.1038/sj.cdd.4402244.

2. Cullen, S.P., Brunet, M., and Martin, S.J. (2010) Granzymes in cancer and immunity, Cell Death Differ., 17, 616–623, doi: 10.1038/cdd.2009.206.

3. Wajant, H. (2014) Principles and mechanisms of CD95 activation, Biol. Chem., 395, 1401–1416, doi: 10.1515/hsz-2014-0212.

4. Siegmund, D., Lang, I., and Wajant, H. (2017) Cell death-independent activities of the death receptors CD95, TRAILR1, and TRAILR2, FEBS J., 284, 1131–1159, doi: 10.1111/febs.13968.

5. Tummers, B., and Green, D.R. (2017) Caspase-8: regulating life and death, Immunol. Rev., 277, 76–89, doi: 10.1111/imr.12541.

6. Vanden Berghe, T., Linkermann, A., Jouan-Lanhouet, S., Walczak, H., and Vandenabeele, P. (2014) Regulated necrosis: the expanding network of non-apoptotic cell death pathways, Nat. Rev. Mol. Cell Biol., 15, 135–147, doi: 10.1038/nrm3737.

7. Tsuchiya, Y., Nakabayashi, O., and Nakano, H. (2015) FLIP the switch: regulation of apoptosis and necroptosis by cFLIP, Int. J. Mol. Sci., 16, 30321–30341, doi: 10.3390/ijms161226232.

8. Zhang, Y., Chen, X., Gueydan, C., and Han, J. (2018) Plasma membrane changes during programmed cell deaths, Cell Res., 28, 9–21, doi: 10.1038/cr.2017.133.

9. Grakoui, A., Bromley, S.K., Sumen, C., Davis, M.M., Shaw, A.S., Allen, P.M., and Dustin, M.L. (1999) The immunological synapse: a molecular machine controlling T cell activation, Science, 285, 221–227, doi: 10.1126/science.285.5425.221.

10. Rousalova, I., and Krepela, E. (2010) Granzyme B-induced apoptosis in cancer cells and its regulation (review), Int. J. Oncol., 37, 1361–1378, doi: 10.3892/ijo_00000788.

11. Woodsworth, D.J., Dunsing, V., and Coombs, D. (2015) Design parameters for granzyme-mediated cytotoxic lymphocyte target-cell killing and specificity, Biophys. J., 109, 477–488, doi: 10.1016/j.bpj.2015.06.045.

12. Podack, E.R., and Munson, G.P. (2016) Killing of microbes and cancer by the immune system with three mammalian pore-forming killer proteins, Front. Immunol., 7, 464, doi: 10.3389/fimmu.2016.00464.

13. Stewart, S.E., D’Angelo, M.E., and Bird, P.I. (2012) Intercellular communication via the endo-lysosomal system: translocation of granzymes through membrane barriers, Biochim. Biophys. Acta, 1824, 59–67, doi: 10.1016/j.bbapap.2011.05.020.

14. Voskoboinik, I., Whisstock, J.C., and Trapani, J.A. (2015) Perforin and granzymes: function, dysfunction and human pathology, Nat. Rev. Immunol., 15, 388–400, doi: 10.1038/nri3839.

15. Andrin, C., Pinkoski, M.J., Burns, K., Atkinson, E.A., Krahenbuhl, O., Hudig, D., Fraser, S.A., Winkler, U., Tschopp, J., Opas, M., Bleackley, R.C., and Michalak, M. (1998) Interaction between a Ca2+-binding protein calreticulin and perforin, a component of the cytotoxic T-cell granules, Biochemistry, 37, 10386–10394, doi: 10.1021/bi980595z.

16. Carafoli, E., and Krebs, J. (2016) Why calcium? How calcium became the best communicator, J. Biol. Chem., 291, 20849–20857, doi: 10.1074/jbc.R116.735894.

17. Davidovich, P., Kearney, C.J., and Martin, S.J. (2014) Inflammatory outcomes of apoptosis, necrosis and necroptosis, Biol. Chem., 395, 1163–1171, doi: 10.1515/hsz-2014-0164.

18. Thiery, J., Keefe, D., Boulant, S., Boucrot, E., Walch, M., Martinvalet, D., Goping, I.S., Bleackley, R.C., Kirchhausen, T., and Lieberman, J. (2011) Perforin pores in the endosomal membrane trigger the release of endocytosed granzyme B into the cytosol of target cells, Nat. Immunol., 12, 770–777, doi: 10.1038/ni.2050.

19. Masson, D., Nabholz, M., Estrade, C., and Tschopp, J. (1986) Granules of cytolytic T-lymphocytes contain two serine esterases, EMBO J., 5, 1595–1600.

20. Masson, D., and Tschopp, J. (1987) A family of serine esterases in lytic granules of cytolytic T lymphocytes, Cell, 49, 679–685, doi: 10.1016/0092-8674(87)90544-7.

21. Susanto, O., Trapani, J.A., and Brasacchio, D. (2012) Controversies in granzyme biology, Tissue Antigens, 80, 477–487, doi: 10.1111/tan.12014.

22. Vahedi, F., Fraleigh, N., Vlasschaert, C., McElhaney, J., and Hanifi-Moghaddam, P. (2014) Human granzymes: related but far apart, Med. Hypotheses, 83, 688–693, doi: 10.1016/j.mehy.2014.09.019.

23. Trapani, J.A. (2001) Granzymes: a family of lymphocyte granule serine proteases, Genome Biol., 2, reviews3014.1–3014.7, doi: 10.1186/gb-2001-2-12-reviews3014.

24. Sutton, V.R., Wowk, M.E., Cancilla, M., and Trapani, J.A. (2003) Caspase activation by granzyme B is indirect, and caspase autoprocessing requires the release of proapoptotic mitochondrial factors, Immunity, 18, 319–329, doi: 10.1016/s1074-7613(03)00050-5.

25. Goping, I.S., Barry, M., Liston, P., Sawchuk, T., Constantinescu, G., Michalak, K.M., Shostak, I., Roberts, D.L., Hunter, A.M., Korneluk, R., and Bleackley, R.C. (2003) Granzyme B-induced apoptosis requires both direct caspase activation and relief of caspase inhibition, Immunity, 18, 355–365, doi: 10.1016/s1074-7613(03)00032-3.

26. Wowk, M.E., and Trapani, J.A. (2004) Cytotoxic activity of the lymphocyte toxin granzyme B, Microbes Infect., 6, 752–758, doi: 10.1016/j.micinf.2004.03.008.

27. Heibein, J.A., Goping, I.S., Barry, M., Pinkoski, M.J., Shore, G.C., Green, D.R., and Bleackley, R.C. (2000) Granzyme B-mediated cytochrome c release is regulated by the Bcl-2 family members Bid and Bax, J. Exp. Med., 192, 1391–1402, doi: 10.1084/jem.192.10.1391.

28. Wang, G.Q., Wieckowski, E., Goldstein, L.A., Gastman, B.R., Rabinovitz, A., Gambotto, A., Li, S., Fang, B., Yin, X.M., and Rabinowich, H. (2001) Resistance to granzyme B-mediated cytochrome c release in Bak-deficient cells, J. Exp. Med., 194, 1325–1337, doi: 10.1084/jem.194.9.1325.

29. Cosentino, K., and Garcia-Saez, A.J. (2017) Bax and Bak pores: Are we closing the circle? Trends Cell Biol., 27, 266–275, doi: 10.1016/j.tcb.2016.11.004.

30. Kale, J., Osterlund, E.J., and Andrews, D.W. (2018) BCL-2 family proteins: changing partners in the dance towards death, Cell Death Differ., 25, 65–80, doi: 10.1038/cdd.2017.186.

31. Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S.M., Ahmad, M., Alnemri, E.S., and Wang, X. (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade, Cell, 91, 479–489, doi: 10.1016/s0092-8674(00)80434-1.

32. Li, J., and Yuan, J. (2008) Caspases in apoptosis and beyond, Oncogene, 27, 6194–6206, doi: 10.1038/onc.2008.297.

33. Dorstyn, L., Akey, C.W., and Kumar, S. (2018) New insights into apoptosome structure and function, Cell Death Differ., 25, 1194–1208, doi: 10.1038/s41418-017-0025-z.

34. Srinivasula, S.M., Ahmad, M., Fernandes-Alnemri, T., and Alnemri, E.S. (1998) Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization, Mol. Cell, 1, 949–957, doi: 10.1016/s1097-2765(00)80095-7.

35. Chang, H.Y., and Yang, X. (2000) Proteases for cell suicide: functions and regulation of caspases, Microbiol. Mol. Biol. Rev., 64, 821–846, doi: 10.1128/mmbr.64.4.821-846.2000.

36. Li, Y., Zhou, M., Hu, Q., Bai, X.-C., Huang, W., Scheres, S.H.W., and Shi, Y. (2017) Mechanistic insights into caspase-9 activation by the structure of the apoptosome holoenzyme, Proc. Natl. Acad. Sci. USA, 114, 1542–1547, doi: 10.1073/pnas.1620626114.

37. Darmon, A.J., Nicholson, D.W., and Bleackley, R.C. (1995) Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B, Nature, 377, 446–448, doi: 10.1038/377446a0.

38. Quan, L.T., Tewari, M., O’Rourke, K., Dixit, V., Snipas, S.J., Poirier, G.G., Ray, C., Pickup, D.J., and Salvesen, G.S. (1996) Proteolytic activation of the cell death protease Yama/CPP32 by granzyme B, Proc. Natl. Acad. Sci. USA, 93, 1972–1976, doi: 10.1073/pnas.93.5.1972.

39. Luthi, A.U., and Martin, S.J. (2007) The CASBAH: a searchable database of caspase substrates, Cell Death Differ., 14, 641–650, doi: 10.1038/sj.cdd.4402103.

40. Julien, O., and Wells, J.A. (2017) Caspases and their substrates, Cell Death Differ., 24, 1380–1389, doi: 10.1038/cdd.2017.44.

41. Han, J., Goldstein, L.A., Gastman, B.R., Froelich, C.J., Yin, X.M., and Rabinowich, H. (2004) Degradation of Mcl-1 by granzyme B: implications for Bim-mediated mitochondrial apoptotic events, J. Biol. Chem., 279, 22020–22029, doi: 10.1074/jbc.M313234200.

42. Han, J., Goldstein, L.A., Gastman, B.R., Rabinovitz, A., and Rabinowich, H. (2005) Disruption of Mcl-1·Bim complex in granzyme B-mediated mitochondrial apoptosis, J. Biol. Chem., 280, 16383–16392, doi: 10.1074/jbc.M411377200.

43. Matsumura, S., Van De Water, J., Kita, H., Coppel, R.L., Tsuji, T., Yamamoto, K., Ansari, A.A., and Gershwin, M.E. (2002) Contribution to antimitochondrial antibody production: cleavage of pyruvate dehydrogenase complex-E2 by apoptosis-related proteases, Hepatology, 35, 14–22, doi: 10.1053/jhep.2002.30280.

44. Siddiqui, W.A., Ahad, A., and Ahsan, H. (2015) The mystery of BCL2 family: Bcl-2 proteins and apoptosis: an update, Arch. Toxicol., 89, 289–317, doi: 10.1007/s00204-014-1448-7.

45. Sarosiek, K.A., Chi, X., Bachman, J.A., Sims, J.J., Montero, J., Patel, L., Flanagan, A., Andrews, D.W., Sorger, P., and Letai, A. (2013) BID preferentially activates BAK while BIM preferentially activates BAX, affecting chemotherapy response, Mol. Cell, 51, 751–765, doi: 10.1016/j.molcel.2013.08.048.

46. Ben Safta, T., Ziani, L., Favre, L., Lamendour, L., Gros, G., Mami-Chouaib, F., Martinvalet, D., Chouaib, S., and Thiery, J. (2015) Granzyme B-activated p53 interacts with Bcl-2 to promote cytotoxic lymphocyte-mediated apoptosis, J. Immunol., 194, 418–428, doi: 10.4049/jimmunol.1401978.

47. Wang, S., Xia, P., Shi, L., and Fan, Z. (2012) FADD cleavage by NK cell granzyme M enhances its self-association to facilitate procaspase-8 recruitment for auto-processing leading to caspase cascade, Cell Death Differ., 19, 605–615, doi: 10.1038/cdd.2011.130.

48. Hou, Q., Zhao, T., Zhang, H., Lu, H., Zhang, Q., Sun, L., and Fan, Z. (2008) Granzyme H induces apoptosis of target tumor cells characterized by DNA fragmentation and Bid-dependent mitochondrial damage, Mol. Immunol., 45, 1044–1055, doi: 10.1016/j.molimm.2007.07.032.

49. Ewen, C.L., Kane, K.P., and Bleackley, R.C. (2013) Granzyme H induces cell death primarily via a Bcl-2-sensitive mitochondrial cell death pathway that does not require direct Bid activation, Mol. Immunol., 54, 309–318, doi: 10.1016/j.molimm.2012.12.020.

50. Shi, L., Wu, L., Wang, S., and Fan, Z. (2009) Granzyme F induces a novel death pathway characterized by Bid-independent cytochrome c release without caspase activation, Cell Death Differ., 16, 1694–1706, doi: 10.1038/cdd.2009.101.

51. Van Damme, P., Maurer-Stroh, S., Hao, H., Colaert, N., Timmerman, E., Eisenhaber, F., Vandekerckhove, J., and Gevaert, K. (2010) The substrate specificity profile of human granzyme A, Biol. Chem., 391, 983–997, doi: 10.1515/BC.2010.096.

52. Beresford, P.J., Zhang, D., Oh, D.Y., Fan, Z., Greer, E.L., Russo, M.L., Jaju, M., and Lieberman, J. (2001) Granzyme A activates an endoplasmic reticulum-associated caspase-independent nuclease to induce single-stranded DNA nicks, J. Biol. Chem., 276, 43285–43293, doi: 10.1074/jbc.M108137200.

53. Fan, Z., Beresford, P.J., Oh, D.Y., Zhang, D., and Lieberman, J. (2003) Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor, Cell, 112, 659–672, doi: 10.1016/s0092-8674(03)00150-8.

54. Martinvalet, D., Zhu, P., and Lieberman, J. (2005) Granzyme A induces caspase-independent mitochondrial damage, a required first step for apoptosis, Immunity, 22, 355–370, doi: 10.1016/j.immuni.2005.02.004.

55. Гривенникова В.Г., Виноградов А.Д. (2003) Митохондриальный комплекс I, Успехи биологической химии, 43, 19–58.

56. Zhu, J., Vinothkumar, K.R., and Hirst, J. (2016) Structure of mammalian respiratory complex I, Nature, 536, 354–358, doi: 10.1038/nature19095.

57. Fiedorczuk, K., Letts, J.A., Degliesposti, G., Kaszuba, K., Skehel, M., and Sazanov, L.A. (2016) Atomic structure of the entire mammalian mitochondrial complex I, Nature, 538, 406–410, doi: 10.1038/nature19794.

58. Martinvalet, D., Dykxhoorn, D.M., Ferrini, R., and Lieberman, J. (2008) Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death, Cell, 133, 681–692, doi: 10.1016/j.cell.2008.03.032.

59. Jacquemin, G., Margiotta, D., Kasahara, A., Bassoy, E.Y., Walch, M., Thiery, J., Lieberman, J., and Martinvalet, D. (2015) Granzyme B-induced mitochondrial ROS are required for apoptosis, Cell Death Differ., 22, 862–874, doi: 10.1038/cdd.2014.180.

60. Ricci, J.E., Muñoz-Pinedo, C., Fitzgerald, P., Bailly-Maitre, B., Perkins, G.A., Yadava, N., Scheffler, I.E., Ellisman, M.H., and Green, D.R. (2004) Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain, Cell, 117, 773–786, doi: 10.1016/j.cell.2004.05.008.

61. Hirst, J., and Roessler, M.M. (2016) Energy conversion, redox catalysis and generation of reactive oxygen species by respiratory complex I, Biochim. Biophys. Acta, 1857, 872–883, doi: 10.1016/j.bbabio.2015.12.009.

62. Rodenburg, R.J. (2016) Mitochondrial complex I-linked disease, Biochim. Biophys. Acta, 1857, 938–945, doi: 10.1016/j.bbabio.2016.02.012.

63. Chiusolo, V., Jacquemin, G., Yonca Bassoy, E., Vinet, L., Liguori, L., Walch, M., Kozjak-Pavlovic, V., and Martinvalet, D. (2017) Granzyme B enters the mitochondria in a Sam50-, Tim22- and mtHsp70-dependent manner to induce apoptosis, Cell. Death Differ., 24, 747–758, doi: 10.1038/cdd.2017.3.

64. Martinvalet, D. (2019) Mitochondrial entry of cytotoxic proteases: a new insight into the granzyme B cell death pathway, Oxid. Med. Cell. Longev., 2019, 9165214, doi: 10.1155/2019/9165214.

65. Grivennikova, V.G., and Vinogradov, A.D. (2006) Generation of superoxide by the mitochondrial complex I, Biochim. Biophys. Acta, 1757, 553–561, doi: 10.1016/j.bbabio.2006.03.013.

66. Murphy, M.P. (2009) How mitochondria produce reactive oxygen species, Biochem. J., 417, 1–13, doi: 10.1042/BJ20081386.

67. Korge, P., Calmettes, G., and Weiss, J.N. (2016) Reactive oxygen species production in cardiac mitochondria after complex I inhibition: modulation by substrate-dependent regulation of the NADH/NAD+ ratio, Free Radic. Biol. Med., 96, 22–33, doi: 10.1016/j.freeradbiomed.2016.04.002.

68. Robb, E.L., Hall, A.R., Prime, T.A., Eaton, S., Szibor, M., Viscomi, C., James, A.M., and Murphy, M.P. (2018) Control of mitochondrial superoxide production by reverse electron transport at complex I, J. Biol. Chem., 293, 9869–9879, doi: 10.1074/jbc.RA118.003647.

69. Shidoji, Y., Hayashi, K., Komura, S., Ohishi, N., and Yagi, K. (1999) Loss of molecular interaction between cytochrome c and cardiolipin due to lipid peroxidation, Biochem. Biophys. Res. Commun., 264, 343–347, doi: 10.1006/bbrc.1999.1410.

70. Kagan, V.E., Tyurin, V.A., Jiang, J., Tyurina, Y.Y., Ritov, V.B., Amoscato, A.A., Osipov, A.N., Belikova, N.A., Kapralov, A.A., Kini, V., Vlasova, I.I., Zhao, Q., Zou, M., Di, P., Svistunenko, D.A., Kurnikov, I.V., and Borisenko, G.G. (2005) Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors, Nat. Chem. Biol., 1, 223–232, doi: 10.1038/nchembio727.

71. Lucken-Ardjomande, S., and Martinou, J.-C. (2008) Granzyme A, a stealth killer in the mitochondrion, Cell, 133, 568–570, doi: 10.1016/j.cell.2008.04.031.

72. Dotiwala, F., Mulik, S., Polidoro, R.B., Ansara, J.A., Burleigh, B.A., Walch, M., Gazzinelli, R.T., and Lieberman, J. (2016) Killer lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites, Nat. Med., 22, 210–216, doi: 10.1038/nm.4023.

73. Kang, S., Brown, H.M., and Hwang, S. (2018) Direct antiviral mechanisms of interferon-gamma, Immune Netw., 18, e33, doi: 10.4110/in.2018.18.e33.

74. Hansen, T.H., and Bouvier, M. (2009) MHC class I antigen presentation: learning from viral evasion strategies, Nat. Rev. Immunol., 9, 503–513, doi: 10.1038/nri2575.

75. Вдовин А.С., Филькин С.Ю., Ефимова П.Р., Шитиков С.А., Капранов Н.М., Давыдова Ю.О., Егоров Е.С., Хамаганова Е.Г., Дроков М.Ю., Кузьмина Л.А., Паровичникова Е.Н., Ефимов Г.А., Савченко В.Г. (2016) Применение рекомбинантных МНС-тетрамеров для изоляции вирусспецифичных CD8+-клеток здоровых доноров: потенциальный подход к клеточной терапии посттранс-плантационной цитомегаловирусной инфекции, Биохимия, 81, 1628–1642, doi: 10.1134/S0006297916110146.

76. Biron, C.A., and Brossay, L. (2001) NK cells and NKT cells in innate defense against viral infections, Curr. Opin. Immunol., 13, 458–464, doi: 10.1016/s0952-7915(00)00241-7.

77. Ruella, M., and Kalos, M. (2014) Adoptive immunotherapy for cancer, Immunol. Rev., 257, 14–38, doi: 10.1111/imr.12136.

78. Kim, N., Lee, H.H., Lee, H.J., Choi, W.S., Lee, J., and Kim, H.S. (2019) Natural killer cells as a promising therapeutic target for cancer immunotherapy, Arch. Pharm. Res., 42, 591–606, doi: 10.1007/s12272-019-01143-y.