Цитотоксичность и неканонические эффекты гистонов – две стороны одной медали

Гистоны являются основными структурными белками хроматина, обеспечивающими упаковку генома и нейтрализацию отрицательного заряда ДНК. Выполнение этих функций обеспечивается высоким содержанием положительно заряженных аминокислот, благодаря чему гистоны эффективно взаимодействуют с нуклеиновыми кислотами и другими отрицательно заряженными молекулами. Роль гистонов не ограничивается организацией структуры хроматина, так как они участвуют в регуляции различных клеточных процессов, включая репликацию, контроль экспрессии генов и репарацию ДНК, а также могут накапливаться вне хроматина, например в ядрышках или цитоплазматических липидных каплях. Кроме того, попадая во внешнюю среду при определенных физиологических и патологических условиях, гистоны способны проявлять выраженную цитотоксичность, повреждая клеточные мембраны, нарушая функционирование органелл и способствуя развитию воспалительных реакций. Такое действие гистонов может приносить пользу,будучи направлено на борьбу с болезнетворными микроорганизмами или вред, если ему подвергаются собственные клетки организма. В данном обзоре обсуждаются современные представления о цитопатическом действии гистонов и их неканонические эффекты, которые мы рассматриваем как следствие положительного заряда этих молекул и их способности взаимодействовать с широким спектром клеточных компонентов

1. Chen P., Li G., Li W. Nucleosome dynamics derived at the single-molecule level bridges its structures and functions. J. Am. Chem. Soc. 2024;4(3):866–876. doi:10.1021/jacsau.3c00658

2. Miloshev G., Ivanov P., Vasileva B., Georgieva M. Linker histones maintain genome stability and drive the process of cellular ageing. Front. Biosci. (Landmark Ed.). 2025;30(4):26823. doi:10.31083/FBL26823

3. Ramaswamy A., Ioshikhes I. Dynamics of modeled oligonucleosomes and the role of histone variant proteins in nucleosome organization. Adv. Protein Chem. Struct. Biol. 2013;90:119–149. doi:10.1016/B978-0-12-410523-2.00004-3

4. Hao F., Kale S., Dimitrov S., Hayes J.J. Unraveling linker histone interactions in nucleosomes. Curr. Opin. Struct. Biol. 2021;71:87–93. doi:10.1016/j.sbi.2021.06.001

5. Martinsen J.H., Saar D., Fernandes C.B., Schuler B., Bugge K., Kragelund B.B. Structure, dynamics, and stability of the globular domain of human linker histone H1.0 and the role of positive charges. Protein Sci. 2022;31(4):918–932. doi:10.1002/pro.4281

6. Grinat J., Shriever N.P., Christophorou M.A. Fantastic proteins and where to find them – histones, in the nucleus and beyond. J. Cell Sci. 2024;137(24):jcs262071. doi:10.1242/jcs.262071

7. Pan Y., Peng M., Tong M., He Y., Hao M., Gao H.L., Lao Y., Xue J., Liu M., Zhong Q., Liu X., Li B. The globular domain of extracellular histones mediates cytotoxicity via membrane disruption mechanism. J. Biol. Chem. 2025;301(1):108038. doi:10.1016/j.jbc.2024.108038

8. Bonner W.M., Wu R.S., Panusz H.T., Muneses C. Kinetics of accumulation and depletion of soluble newly synthesized histone in the reciprocal regulation of histone and DNA synthesis. Biochemistry. 1988;27(17):6542–6550. doi:10.1021/bi00417a052

9. Oliver D., Granner D, Chalkley R. Identification of a distinction between cytoplasmic histone synthesis and subsequent histone deposition within the nucleus. Biochemistry. 1974;13(4):746–749. doi:10.1021/bi00701a017

10. Zhang Y., Zhang Q., Zhang Y., Han J. The role of histone modification in DNA replication-coupled nucleosome assembly and cancer. Int. J. Mol. Sci. 2023;24(5):4939. doi:10.3390/ijms24054939

11. Gunjan A., Paik J., Verreault A. The emergence of regulated histone proteolysis. Curr. Opin. Genet. Dev. 2006;16(2):112–118. doi:10.1016/j.gde.2006.02.010

12. Singh R.K., Kabbaj M-H.M., Paik J., Gunjan A. Histone levels are regulated by phosphorylation and ubiquitylation-dependent proteolysis. Nat. Cell Biol. 2009;11(8):925–933. doi:10.1038/ncb1903

13. Hammond C.M., Strømme C.B., Huang H., Patel D.J., Groth A. Histone chaperone networks shaping chromatin function. Nat. Rev. Mol. Cell Biol. 2017;18(3):141–158. doi:10.1038/nrm.2016.159

14. Mattiroli F., D’Arcy S., Luger K. The right place at the right time: chaperoning core histone variants. EMBO Rep. 2015;16(11):1454–1466. doi:10.15252/embr.201540840

15. Pardal A.J, Fernandes-Duarte F., Bowman A.J. The histone chaperoning pathway: from ribosome to nucleosome. Essays Biochem. 2019;63(1):29–43. doi:10.1042/EBC20180055

16. Torres-Arciga K., Flores-León M., Ruiz-Pérez S., Trujillo-Pineda M., González-Barrios R., Herrera L.A. Histones and their chaperones: Adaptive remodelers of an ever-changing chromatinic landscape. Front. Genet. 2022;13:1057846. doi:10.3389/fgene.2022.1057846

17. Burgess R.J., Zhang Z. Histone chaperones in nucleosome assembly and human disease. Nat. Struct. Mol. Biol. 2013;20(1):14–22. doi:10.1038/nsmb.2461

18. Liu C-P., Xu R-M. Structure and function of histone chaperones in replication-coupled chromatin assembly. Curr. Opin. Struct. Biol. 2025;92:103059. doi:10.1016/j.sbi.2025.103059

19. Han M., Chang M., Kim U.J., Grunstein M. Histone H2B repression causes cell-cycle-specific arrest in yeast: effects on chromosomal segregation, replication, and transcription. Cell. 1987;48(4):589–597. doi:10.1016/0092-8674(87)90237-6

20. Meeks-Wagner D., Hartwell L.H. Normal stoichiometry of histone dimer sets is necessary for high fidelity of mitotic chromosome transmission. Cell. 1986;44(1):43–52. doi:10.1016/0092-8674(86)90483-6

21. Gunjan A., Verreault A. A Rad53 kinase-dependent surveillance mechanism that regulates histone protein levels in S. cerevisiae. Cell. 2003;115(5):537–549. doi:10.1016/s0092-8674(03)00896-1

22. Singh R.K., Liang D., Gajjalaiahvari U.R., Kabbaj M-H.M., Paik J., Gunjan A. Excess histone levels mediate cytotoxicity via multiple mechanisms. Cell Cycle. 2010;9(20):4236–4244. doi:10.4161/cc.9.20.13636

23. Buttress T., He S., Wang L., Zhou S., Saalbach G., Vickers M., Li G., Li P., Feng X. Histone H2B.8 compacts flowering plant sperm through chromatin phase separation. Nature. 2022;611(7936):614–622. doi:10.1038/ s41586-022-05386-6

24. Liang D., Burkhart S.L., Singh R.K., Kabbaj M-H.M., Gunjan A. Histone dosage regulates DNA damage sensitivity in a checkpoint-independent manner by the homologous recombination pathway. Nucleic Acids Res. 2012;40(19):9604–9620. doi:10.1093/nar/gks722

25. Phillips E.O.N., Gunjan A. Histone variants: The unsung guardians of the genome. DNA Repair (Amst.). 2022;112:103301. doi:10.1016/j.dnarep.2022.103301

26. Glowczewski L., Yang P., Kalashnikova T., Santisteban M.S., Smith M.M. Histone-histone interactions and centromere function. Mol. Cell. Biol. 2000;20(15):5700–5711. doi:10.1128/MCB.20.15.5700-5711.2000

27. Au W-C., Crisp M.J., DeLuca S.Z., Rando O.J., Basrai M.A. Altered dosage and mislocalization of histone H3 and Cse4p lead to chromosome loss in Saccharomyces cerevisiae. Genetics. 2008;179(1):263–275. doi:10.1534/genetics.108.088518

28. Hu Z., Chen K., Xia Z., Chavez M., Pal S., Seol J-H., Chen C.C., Li W., Tyler J.K. Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging. Genes Dev. 2014;28(4):396–408. doi:10.1101/gad.233221.113

29. Bhaud Y., Guillebault D., Lennon J., Defacque H., Soyer-Gobillard M.O., Moreau H. Morphology and behaviour of dinoflagellate chromosomes during the cell cycle and mitosis. J. Cell Sci. 2000;113 (Pt. 7):1231–1239. doi:10.1242/jcs.113.7.1231

30. Moreno Díaz de la Espina S., Alverca E., Cuadrado A., Franca S. Organization of the genome and gene expression in a nuclear environment lacking histones and nucleosomes: the amazing dinoflagellates. Eur. J. Cell Biol. 2005;84(2–3):137–149. doi:10.1016/j.ejcb.2005.01.002

31. Golyshev S., A.N., Berdieva M., Musinova Y., Sheval E., Skarlato S. Ultrastructural organization of the chromatin elements in chromosomes of the dinoflagellate Prorocentrum minimum. Protistology. 2018;12(4)163–172. doi:10.21685/1680-0826-2018-12-4-1

32. Rizzo P.J., Noodén L.D. Chromosomal proteins in the dinoflagellate alga Gyrodinium cohnii. Science. 1972;176(4036):796–797. doi:10.1126/science.176.4036.796

33. Kato K.H., Moriyama A., Huitorel P., Cosson J., Cachon M., Sato H. Isolation of the major basic nuclear protein and its localization on chromosomes of the dinoflagellate, Oxyrrhis marina. Biol. Cell. 1997;89(1):43–52. doi:10.1016/s0248-4900(99)80080-x

34. Gornik S.G., Ford K.L., Mulhern T.D., Bacic A., McFadden G.I, Waller R.F. Loss of nucleosomal DNA condensation coincides with appearance of a novel nuclear protein in dinoflagellates. Curr. Biol. 2012;22(24):2303–2312. doi:10.1016/j.cub.2012.10.036

35. Janouškovec J., Gavelis G.S., Burki F., Dinh D., Bachvaroff T.R., Gornik S.G., et al. Major transitions in dinoflagellate evolution unveiled by phylotranscriptomics. Proc. Natl. Acad. Sci. U.S.A. 2017;114(2):E171–E180. doi:10.1073/pnas.1614842114

36. Talbert P.B., Henikoff S. Chromatin: packaging without nucleosomes. Curr. Biol. 2012;22(24):R1040– R1043. doi:10.1016/j.cub.2012.10.052

37. Kalvelage J., Wöhlbrand L., Schoon R-A., Zink F-M., Correll C., Senkler J., Eubel H., Hoppenrath M., Rhiel E., Braun H.P., Winklhofer M., Klingl A., Rabus R. The enigmatic nucleus of the marine dinoflagellate Prorocentrum cordatum. mSphere. 2023;8(4):e0003823. doi:10.1128/msphere.00038-23

38. Shoguchi E., Shinzato C., Kawashima T., et al. Draft assembly of the Symbiodinium minutum nuclear genome reveals dinoflagellate gene structure. Curr. Biol. 2013;23(15):1399–1408. doi:10.1016/j.cub.2013.05.062

39. Lin S., Zhang H., Zhuang Y., Tran B., Gill J. Spliced leader-based metatranscriptomic analyses lead to recognition of hidden genomic features in dinoflagellates. Proc. Natl. Acad. Sci. U.S.A. 2010;107(46):20033–20038. doi:10.1073/pnas.1007246107

40. Roy S., Morse D. A full suite of histone and histone modifying genes are transcribed in the dinoflagellate Lingulodinium. PLoS One. 2012;7(4):e34340. doi:10.1371/journal. pone.0034340

41. Marinov G.K., Lynch M. Diversity and divergence of dinoflagellate histone proteins. G3: Genes Genomes Genet. 2015;6(2):397–422. doi:10.1534/g3.115.023275

42. Riaz S., Sui Z. Molecular cloning, transcript profiling, and characterization of histone genes in the dinoflagellate Alexandrium pacificum. J. Microbiol. Biotechnol. 2018;28(7):1185–1198. doi:10.4014/jmb.1802.01075

43. Riaz S., Niaz Z., Khan S., Liu Y., Sui Z. Detection, characterization and expression dynamics of histone proteins in the dinoflagellate Alexandrium pacificum during growth regulation. Harmful Algae. 2019;87(1):101630. doi:10.1016/j. hal.2019.101630

44. Irwin N.A.T., Martin B.J.E., Young B.P., Browne M.J.G., Flaus A., Loewen C.J.R., Keeling P.J., Howe L.J. Viral proteins as a potential driver of histone depletion in dinoflagellates. Nat. Commun. 2018;9(1):1535. doi:10.1038/s41467-018-03993-4

45. di Padua Mathieu D., Mura C.V., Frado L.L., Woodcock C.L., Stollar B.D. Differing accessibility in chromatin of the antigenic sites of regions 1-58 and 63-125 of histone H2B. J. Cell Biol. 1981;91(1):135–141. doi:10.1083/jcb.91.1.135

46. Kalashnikova A.A., Winkler D.D., McBryant S.J., Henderson R.K., Herman J.A., DeLuca J.G., et al. Linker histone H1.0 interacts with an extensive network of proteins found in the nucleolus. Nucleic Acids Res. 2013;41(7):4026–4035. doi:10.1093/nar/gkt104

47. Szerlong H.J., Herman J.A., Krause C.M., DeLuca J.G., Skoultchi A., Winger Q.A., Prenni J.E., Hansen J.C. Proteomic characterization of the nucleolar linker histone H1 interaction network. J. Mol. Biol. 2015;427(11):2056–2071. doi:10.1016/j.jmb.2015.01.001

48. Chen J., Teo B.H.D., Cai Y., Wee S.Y.K., Lu J. The linker histone H1.2 is a novel component of the nucleolar organizer regions. J. Biol. Chem. 2018;293(7):2358–2369. doi:10.1074/jbc.M117.810184

49. Cong R., Das S., Douet J., Wong J., Buschbeck M., Mongelard F., Bouvet P. macroH2A1 histone variant represses rDNA transcription. Nucleic Acids Res. 2014;42(1):181–192. doi:10.1093/nar/gkt863

50. Musinova Y.R., Lisitsyna O.M., Golyshev S.A., Tuzhikov A.I., Polyakov V.Y., Sheval E.V. Nucleolar localization/retention signal is responsible for transient accumulation of histone H2B in the nucleolus through electrostatic interactions. Biochim. Biophys. Acta. 2011;1813(1):27–38. doi:10.1016/j.bbamcr.2010.11.003

51. Apta-Smith M.J., Hernandez-Fernaud J.R., Bowman A.J. Evidence for the nuclear import of histones H3.1 and H4 as monomers. EMBO J. 2018;37(19):e98714. doi:10.15252/embj.201798714

52. Safina A., Cheney P., Pal M., Brodsky L., Ivanov A., Kirsanov K., Lesovaya E., Naberezhnov D., Nesher E., Koman I., Wang D., Wang J., Yakubovskaya M., Winkler D., Gurova K. FACT is a sensor of DNA torsional stress in eukaryotic cells. Nucleic Acids Res. 2017;45(4):1925–1945. doi:10.1093/nar/gkw1366

53. Nesher E., Safina A., Aljahdali I., Portwood S., Wang E.S., Koman I., Wang J., Gurova K.V. Role of chrotin damage and chromatin trapping of FACT in mediating the anticancer cytotoxicity of DNA-binding small-molecule drugs. Cancer Res. 2018;78(6):1431–1443. doi:10.1158/0008-5472.CAN-17-2690

54. Wang P., Jiang H., Boeren S., Dings H., Kulikova O., Bisseling T., Limpens E. A nuclear-targeted effector of Rhizophagus irregularis interferes with histone 2B mono-ubiquitination to promote arbuscular mycorrhisation. New Phytol. 2021;230(3):1142–1155. doi:10.1111/nph.17236

55. Carmo-Fonseca M., Mendes-Soares L., Campos I. To be or not to be in the nucleolus. Nat. Cell Biol. 2000;2(6):E107–12. doi:10.1038/35014078

56. Phair RD, Misteli T. High mobility of proteins in the mammalian cell nucleus. Nature. 2000;404(6778):604–609. doi:10.1038/35007077

57. Chen D., Huang S. Nucleolar components involved in ribosome biogenesis cycle between the nucleolus and nucleoplasm in interphase cells. J. Cell Biol. 2001;153(1):169–176. doi:10.1083/jcb.153.1.169

58. Emmott E., Hiscox J.A. Nucleolar targeting: the hub of the matter. EMBO Rep. 2009;10(3):231–238. doi:10.1038/embor.2009.14

59. Ishii S., Kakizuka T., Park S-J., Tagawa A., Sanbo C., Tanabe H., Ohkawa Y., Nakanishi M., Nakai K., Miyanari Y. Genome-wide ATAC-see screening identifies TFDP1 as a modulator of global chromatin accessibility. Nat. Genet. 2024;56(3):473–482. doi:10.1038/s41588-024-01658-1

60. Savada R.P., Bonham-Smith P.C. Charge versus sequence for nuclear/nucleolar localization of plant ribosomal proteins. Plant Mol. Biol. 2013;81(4–5):477–493. doi:10.1007/s11103-013-0017-4

61. Musinova Y.R., Kananykhina E.Y., Potashnikova D.M., Lisitsyna O.M., Sheval E.V. A charge-dependent mechanism is responsible for the dynamic accumulation of proteins inside nucleoli. Biochim. Biophys. Acta. 2015;1853(1):101–110. doi:10.1016/j.bbamcr.2014.10.007

62. Martin R.M., Ter-Avetisyan G., Herce H.D., Ludwig A.K., Lättig-Tünnemann G., Cardoso M.C. Principles of protein targeting to the nucleolus. Nucleus. 2015;6(4):314–325. doi:10.1080/19491034.2015.1079680

63. Rashid F-Z.M., Mahlandt E., van der Vaart M., et al. HI-NESS: a family of genetically encoded DNA labels based on a bacterial nucleoid-associated protein. Nucleic Acids Res. 2022;50(2):e10. doi:10.1093/nar/gkab993

64. Liu Y., Wang Y., Yang L., Sun F., Li S., Wang Y., Zhang G.A., Dong T., Zhang L.L., Duan W., Zhang X., Cui W., Chen S. The nucleolus functions as the compartment for histone H2B protein degradation. iScience. 2021;24(4):102256. doi:10.1016/j.isci.2021.102256

65. Sen Gupta A., Joshi G., Pawar S., Sengupta K. Nucleolin modulates compartmentalization and dynamics of histone 2B-ECFP in the nucleolus. Nucleus. 2018;9(1):350– 367. doi:10.1080/19491034.2018.1471936

66. Angelov D., Bondarenko V.A., Almagro S., Menoni H., Mongélard F., Hans F., Mietton F., Studitsky V.M., Hamiche A., Dimitrov S., Bouvet P. Nucleolin is a histone chaperone with FACT-like activity and assists remodeling of nucleosomes. EMBO J. 2006;25(8):1669–1679. doi:10.1038/sj.emboj.7601046

67. Okuwaki M., Matsumoto K., Tsujimoto M., Nagata K. Function of nucleophosmin/B23, a nucleolar acidic protein, as a histone chaperone. FEBS Lett. 2001;506(3):272–276. doi:10.1016/s0014-5793(01)02939-8

68. Swaminathan V., Kishore A.H., Febitha K.K., Kundu T.K. Human histone chaperone nucleophosmin enhances acetylation-dependent chromatin transcription. Mol. Cell. Biol. 2005;25(17):7534–7545. doi:10.1128/MCB.25.17.7534-7545.2005

69. King M.R., Ruff K.M., Lin A.Z., Pant A., Farag M., Lalmansingh J.M., Wu T., Fossat M.J., Ouyang W., Lew M.D., Lundberg E., Vahey M.D., Pappu R.V. Macromolecular condensation organizes nucleolar sub-phases to set up a pH gradient. Cell. 2024;187(8):1889–1906.e24. doi:10.1016/j.cell.2024.02.029

70. Lechertier T., Sirri V., Hernandez-Verdun D., Roussel P. A B23-interacting sequence as a tool to visualize protein interactions in a cellular context. J. Cell Sci. 2007;120(Pt. 2):265–275. doi:10.1242/jcs.03345

71. Wang Y., Chen B., Li Y., Zhou D., Chen S. PNRC accumulates in the nucleolus by interaction with B23/nucleophosmin via its nucleolar localization sequence. Biochim. Biophys. Acta. 2011;1813(1):109–119. doi:10.1016/j.bbamcr.2010.09.017

72. Zhou J., Qiu Y., Zhu N., Zhou L., Dai B., Feng X., Hou L., Liu J. The nucleolar localization signal of porcine Circovirus type 4 capsid protein is essential for interaction with Serine-48 residue of nucleolar phosphoprotein nucleophosmin-1. Front. Microbiol. 2021;12:751382. doi:10.3389/fmicb.2021.751382

73. Shrikondawar A.N., Chennoju K., Ghosh D.K., Ranjan A. Identification and functional characterization of the nuclear and nucleolar localization signals in the intrinsically disordered region of nucleomethylin. J. Cell. Physiol. 2024;239(12):e31433. doi:10.1002/jcp.31433

74. Dueva R., Akopyan K., Pederiva C., Trevisan D., Dhanjal S., Lindqvist A., et al. Neutralization of the positive charges on histone tails by RNA promotes an open chromatin structure. Cell Chem. Biol. 2019;26(10):1436–1449.e5. doi:10.1016/j.chembiol.2019.08.002

75. Mondal T., Rasmussen M., Pandey G.K., Isaksson A., Kanduri C. Characterization of the RNA content of chromatin. Genome Res. 2010;20(7):899–907. doi:10.1101/gr.103473.109

76. Ryabykh G.K., Mylarshchikov D.E., Kuznetsov S.V., Sigorskikh A.I., Ponomareva T.Y., Zharikova A.A., Mironov A.A. RNA-chromatin interactome: What? Where? When? Mol. Biol. (Mosk.). 2022;56(2):275–295. doi:10.31857/S002689842202015X

77. Palihati M., Saitoh N. RNA in chromatin organization and nuclear architecture. Curr. Opin. Genet. Dev. 2024;86:102176. doi:10.1016/j.gde.2024.102176

78. Kuang S., Pollard K.S. Exploring the roles of RNAs in chromatin architecture using deep learning. Nat. Commun. 2024;15(1):6373. doi:10.1038/s41467-024-50573-w

79. Quinodoz S.A., Jachowicz J.W., Bhat P., Ollikainen N., Banerjee A.K., Goronzy I.N., Blanco M.R., Chovanec P., Chow A., Markaki Y., Thai J., Plath K., Guttman M. RNA promotes the formation of spatial compartments in the nucleus. Cell. 2021;184(23):5775–5790.e30. doi:10.1016/j.cell.2021.10.014

80. Zvezdin D.S., Tyukaev A.A., Zharikova A.A., Mironov A.A. A joint analysis of RNA-DNA and DNADNA interactomes reveals their strong association. Int. J. Mol. Sci. 2025;26(3):1137. doi:10.3390/ijms26031137

81. García-Gimenez J.L., Ruiz-Rodríguez J.C., Ferrer R., et al. Circulating histones as clinical biomarkers in critically ill conditions. FEBS Lett. 2025;599(22):3174-3195. doi:10.1002/1873-3468.70093

82. Reiner L., de Beer E.J., Green M. Toxic effects of some basic proteins. Exp. Biol. Med. (Maywood). 1942;50(1):70–74. doi:10.3181/00379727-50-13701

83. Miller B.F., Abrams R., Dorfman A., Klein M. Antibacterial properties of protamine and histone. Science. 1942;96(2497):428–430. doi:10.1126/science.96.2497.428

84. Xu Z., Huang Y., Mao P., Zhang J., Li Y. Sepsis and ARDS: The dark side of histones. Mediators Inflamm. 2015;2015(1):205054. doi:10.1155/2015/205054

85. Xu J., Zhang X., Pelayo R., Monestier M., Ammollo C.T., Semeraro F., Taylor F.B., Esmon N.L., Lupu F., Esmon C.T. Extracellular histones are major mediators of death in sepsis. Nat. Med. 2009;15(11):1318–1321. doi:10.1038/nm.2053

86. Xu J., Zhang X., Monestier M., Esmon N.L., Esmon C.T. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J. Immunol. 2011;187(5):2626–2631. doi:10.4049/jimmunol.1003930

87. Huang H., Evankovich J., Yan W., Nace G., Zhang L., Ross M., Liao X., Billiar T., Xu J., Esmon C.T., Tsung A. Endogenous histones function as alarmins in sterile inflammatory liver injury through Toll-like receptor 9 in mice. Hepatology. 2011;54(3):999–1008. doi:10.1002/hep.24501

88. Jung J., Lee L.E., Kim H., Kim J.E., Jang S.H., Roh J.S., Lee B., Robinson W.H., Sohn D.H., Pyun J.C., Song J.J. Extracellular histones aggravate autoimmune arthritis by lytic cell death. Front. Immunol. 2022;13:961197. doi:10.3389/fimmu.2022.961197

89. Yong J., Abrams S.T., Wang G., Toh C-H. Cellfree histones and the cell-based model of coagulation. J. Thromb. Haemost. 2023;21(7):1724–1736. doi:10.1016/j. jtha.2023.04.018

90. Abrams S.T., Alhamdi Y., Zi M., Guo F., Du M., Wang G., Cartwright E.J., Toh C.H. Extracellular histone-induced protein kinase C alpha activation and troponin phosphorylation is a potential mechanism of cardiac contractility depression in sepsis. Int. J. Mol. Sci. 2023;24(4):3225. doi:10.3390/ijms24043225

91. Wang Z., Wang L., Cao C., Jin H., Zhang Y., Liu Y., Gao Y., Liang X., Li G., Shou S. Heparin attenuates histone-mediated cytotoxicity in septic acute kidney injury. Front. Med. (Lausanne). 2020;7:586652. doi:10.3389/fmed.2020.586652

92. Shi C-X., Wang Y., Chen Q., Jiao F-Z., Pei M-H., Gong Z-J. Extracellular histone H3 induces pyroptosis during sepsis and may act through NOD2 and VSIG4/NLRP3 pathways. Front. Cell. Infect. Microbiol. 2020;10:196. doi:10.3389/fcimb.2020.00196

93. Beltrán-García J., Osca-Verdegal R., Pérez-Cremades D., Novella S., Hermenegildo C., Pallardó F.V., García-Giménez J.L. Extracellular histones activate endothelial NLRP3 inflammasome and are associated with a severe sepsis phenotype. J. Inflamm. Res. 2022;15:4217–4238. doi:10.2147/JIR.S363693

94. Abrams S.T., Zhang N., Manson J., Liu T., Dart C., Baluwa F., Wang S.S., Brohi K., Kipar A., Yu W., Wang G., Toh C.H. Circulating histones are mediators of trauma-associated lung injury. Am. J. Respir. Crit. Care Med. 2013;187(2):160–169. doi:10.1164/rccm.201206-1037OC

95. Abrams S.T., Su D., Sahraoui Y., Lin Z., Cheng Z., Nesbitt K., et al. Assembly of alternative prothrombinase by extracellular histones initiate and disseminate intravascular coagulation. Blood. 2020;137(1):103–114. doi:10.1182/blood.2019002973

96. Semeraro F., Ammollo C.T., Morrissey J.H., Dale G.L., Friese P., Esmon N.L., Esmon C.T. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood. 2011;118(7):1952–1961. doi:10.1182/ blood-2011-03-343061

97. Ashar H.K., Mueller N.C., Rudd J.M., Snider T.A., Achanta M., Prasanthi M., Pulavendran S., Thomas P.G., Ramachandran A., Malayer J.R., Ritchey J.W., Rajasekhar R., Chow V.T.K., Esmon C.T., Teluguakula N. The role of extracellular histones in influenza virus pathogenesis. Am. J. Pathol. 2018;188(1):135–148. doi:10.1016/j.ajpath.2017.09.014

98. Gilthorpe J.D., Oozeer F., Nash J., Calvo M., Bennett D.L., Lumsden A., Pini A. Extracellular histone H1 is neurotoxic and drives a pro-inflammatory response in microglia. F1000Res. 2013;2:148. doi:10.12688/f1000research.2-148.v1

99. Kawano H., Ito T., Yamada S., Hashiguchi T., Maruyama I., Hisatomi T., Nakamura M., Sakamoto T. Toxic effects of extracellular histones and their neutralization by vitreous in retinal detachment. Lab. Invest. 2014;94:569–585. doi:10.1038/labinvest.2014.46

100. Marsman G., von Richthofen H., Bulder I., Lupu F., Hazelzet J., Luken B.M., Zeerleder S. DNA and factor VII-activating protease protect against the cytotoxicity of histones. Blood Adv. 2017;1(26):2491–2502. doi:10.1182/bloodadvances.2017010959

101. Augusto J-F., Beauvillain C., Poli C., et al. Clusterin neutralizes the inflammatory and cytotoxic properties of extracellular histones in sepsis. Am. J. Respir. Crit. Care Med. 2023;208(2):176–187. doi:10.1164/rccm.202207-1253OC

102. Hirsch J.G. Bactericidal action of histone. J. Exp. Med. 1958;108(6):925–944. doi:10.1084/jem.108.6.925

103. Thiam H.R., Wong S.L., Wagner D.D., Waterman C.M. Cellular mechanisms of NETosis. Annu Rev. Cell Dev. Biol. 2020;36:191–218. doi:10.1146/annurevcellbio-020520-111016

104. Asaba C.N., Gwanyama B.N., Ayuk H.S., Odo T.I., Bitazar R., Noumi T., Labonté P., Bukong T.N. Neutrophil extracellular traps in viral infections: Regulation, immune consequences, and pathogenic outcomes. Cells. 2026;15(7):580. doi:10.3390/cells15070580

105. Tsourouktsoglou T.D., Warnatsch A., Ioannou M., Hoving D., Wang Q., Papayannopoulos V. Histones, DNA, and citrullination promote neutrophil extracellular trap inflammation by regulating the localization and activation of TLR4. Cell Rep. 2020;31(5):107602. doi:10.1016/j.celrep.2020.107602

106. Zhou P., Li T., Jin J., Liu Y., Li B., Sun Q., Tian J., Zhao H., Liu Z., Ma S., Zhang S., Novakovic V.A., Shi J., Hu S. Interactions between neutrophil extracellular traps and activated platelets enhance procoagulant activity in acute stroke patients with ICA occlusion. EBioMedicine. 2020;53:102671. doi:10.1016/j.ebiom.2020.102671

107. Luo H., Guo H., Zhou Y., Fang R., Zhang W., Mei Z. Neutrophil extracellular traps in cerebral ischemia/reperfusion injury: Friend and foe. Curr Neuropharmacol. 2023;21(10):2079–96. doi:10.2174/1570159X21666230308090351

108. Thålin C., Hisada Y., Lundström S., Mackman N., Wallén H. Neutrophil extracellular traps: Villains and targets in arterial, venous, and cancer-associated thrombosis. Arterioscler. Thromb. Vasc. Biol. 2019;39(9):1724–1738. doi:10.1161/ATVBAHA.119.312463

109. Schattner M. Platelet TLR4 at the crossroads of thrombosis and the innate immune response. J. Leukoc. Biol. 2019;105(5):873–880. doi:10.1002/JLB.MR0618-213R

110. Toh J.M., Yong J., Abrams S.T., Wang L., Schofield J., Lane S., La Corte A.C., Wang S.S., Ariëns R.A.S, Philippou H., Xie J., Yu W., Wang G., Toh C.H. Fibrinogen binding to histones in circulation protects against adverse cellular and clinical outcomes. J. Thromb. Haemost. 2024;22(8):2247–60. doi:10.1016/j.jtha.2024.05.009

111. Clark S.R., Ma A.C., Tavener S.A., et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat. Med. 2007;13(4):463–469. doi:10.1038/nm1565

112. Maugeri N., Campana L., Gavina M., Covino C., De Metrio M., Panciroli C., Maiuri L., Maseri A., D’Angelo A., Bianchi M.E., Rovere-Querini P., Manfredi A.A. Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. J. Thromb. Haemost. 2014;12(12):2074–88. doi:10.1111/jth.12710

113. Etulain J., Martinod K., Wong S.L., Cifuni S.M., Schattner M., Wagner D.D. P-selectin promotes neutrophil extracellular trap formation in mice. Blood. 2015;126(2):242–246. doi:10.1182/blood-2015-01-624023

114. Tagai C., Morita S., Shiraishi T., Miyaji K., Iwamuro S. Antimicrobial properties of arginine- and lysine-rich histones and involvement of bacterial outer membrane protease T in their differential mode of actions. Peptides. 2011;32(10):2003–2009. doi:10.1016/j.peptides.2011.09.005

115. Doolin T., Amir H.M., Duong L., Rosenzweig R., Urban L.A., Bosch M., Pol A., Gross S.P., Siryaporn A. Mammalian histones facilitate antimicrobial synergy by disrupting the bacterial proton gradient and chromosome organization. Nat. Commun. 2020;11(1):3888. doi:10.1038/ s41467-020-17699-z

116. Rose F.R., Bailey K., Keyte J.W., Chan W.C., Greenwood D., Mahida Y.R. Potential role of epithelial cell-derived histone H1 proteins in innate antimicrobial defense in the human gastrointestinal tract. Infect. Immun. 1998;66(7):3255–3263. doi:10.1128/IAI.66.7.3255-3263.1998

117. Kim H.S., Cho J.H., Park H.W., Yoon H., Kim M.S., Kim S.C. Endotoxin-neutralizing antimicrobial proteins of the human placenta. J. Immunol. 2002;168(5):2356–2364. doi:10.4049/jimmunol.168.5.2356

118. Lee D-Y., Huang C-M., Nakatsuji T., Thiboutot D., Kang S-A., Monestier M., Gallo R.L. Histone H4 is a major component of the antimicrobial action of human sebocytes. J. Invest. Dermatol. 2009;129(10):2489–2496.doi:10.1038/jid.2009.106

119. Cermelli S., Guo Y., Gross S.P., Welte M.A. The lipid-droplet proteome reveals that droplets are a protein-storage depot. Curr. Biol. 2006;16(18):1783–1795.doi:10.1016/j.cub.2006.07.062

120. Lagrutta L.C., Layerenza J.P., Bronsoms S., Trejo S.A., Ves-Losada A. Nuclear-lipid-droplet proteome: carboxylesterase as a nuclear lipase involved in lipid-droplet homeostasis. Heliyon. 2021;7(3):e06539. doi:10.1016/j. heliyon.2021.e06539

121. Anand P., Cermelli S., Li Z., Kassan A., Bosch M., Sigua R., Huang L., Ouellette A.J., Pol A., Welte M.A., Gross S.P. A novel role for lipid droplets in the organismal antibacterial response. Elife. 2012;1:e00003. doi:10.7554/eLife.00003

122. Smolenski G., Haines S., Kwan F.Y-S., Bond J., Farr V., Davis S.R., Stelwagen K., Wheeler T.T. Characterisation of host defence proteins in milk using a proteomic approach. J. Proteome Res. 2007;6(1):207–215. doi:10.1021/pr0603405

123. Wan H-C., Melo R.C.N., Jin Z., Dvorak A.M., Weller P.F. Roles and origins of leukocyte lipid bodies: proteomic and ultrastructural studies. FASEB J. 2007;21(1):167–178. doi:10.1096/fj.06-6711com

124. Larsson S., Resjö S., Gomez M.F., James P., Holm C. Characterization of the lipid droplet proteome of a clonal insulin-producing β-cell line (INS-1 832/13). J. Proteome Res. 2012;11(2):1264–1273. doi:10.1021/pr200957p

125. Kim H.S., Yoon H., Minn I., Park C.B., Lee W.T., Zasloff M., Kim S.C. Pepsin-mediated processing of the cytoplasmic histone H2A to strong antimicrobial peptide buforin I. J. Immunol. 2000;165(6):3268–3274. doi:10.4049/ jimmunol.165.6.3268

126. Kawasaki H., Iwamuro S. Potential roles of histones in host defense as antimicrobial agents. Infect. Disord. Drug Targets. 2008;8(3):195–205. doi:10.2174/1871526510808030195

127. Melnikov S., Kwok H-S., Manakongtreecheep K., van den Elzen A., Thoreen C.C., Söll D. Archaeal ribosomal proteins possess nuclear localization signal-type motifs: Implications for the origin of the cell nucleus. Mol. Biol. Evol. 2020;37(1):124–133. doi:10.1093/molbev/msz207

128. Lisitsyna O.M,. Kurnaeva M.A., Arifulin E.A., Shubina M.Y., Musinova Y.R., Mironov A.A., Sheval E.V. Origin of the nuclear proteome on the basis of pre-existing nuclear localization signals in prokaryotic proteins. Biol. Direct. 2020;15(1):9. doi:10.1186/s13062-020-00263-6

129. Bernardes N.E., Chook Y.M. Nuclear import of histones. Biochem. Soc. Trans. 2020;48(6):2753–2767. doi:10.1042/BST20200572

130. Jäkel S., Mingot J-M., Schwarzmaier P., Hartmann E., Görlich D. Importins fulfil a dual function as nuclear import receptors and cytoplasmic chaperones for exposed basic domains. EMBO J. 2002;21(3):377–386. doi:10.1093/emboj/21.3.377

131. Padavannil A., Sarkar P., Kim S.J., Cagatay T., Jiou J., Brautigam C.A., Tomchick D.R., Sali A., D’Arcy S., Chook Y.M. Importin-9 wraps around the H2A-H2B core to act as nuclear importer and histone chaperone. Elife. 2019;8:e43630. doi:10.7554/eLife.43630

132. Bernardes N.E., Fung H.Y.J., Li Y., Chen Z., Chook Y.M. Structure of IMPORTIN-4 bound to the H3-H4-ASF1 histone-histone chaperone complex. Proc. Natl. Acad. Sci. U.S.A. 2022;119(38):e2207177119.doi:10.1073/pnas.2207177119

133. Fung H.Y.J., Jiou J., Niesman A.B., Bernardes N.E., Chook Y.M. Nap1 and Kap114 co-chaperone H2A-H2B and facilitate targeted histone release in the nucleus. J. Cell Biol. 2025;224(1): e202408193. doi:10.1083/jcb.202408193