BRCA1 Regulates IFI16 Mediated Nuclear Innate Sensing of Herpes Viral DNA and Subsequent Induction of the Innate Inflammasome and Interferon-β Responses

English version České info

Invasion of a host cell by pathogens, including viruses, is sensed by pattern-recognition receptors resulting in the elicitation of the host innate defenses such as the formation of multi-protein inflammasome complexes, inflammatory IL-1β and IL-18 cytokine production and interferon-β production via the cytoplasmic STING molecule. We have shown that nuclear episomal viral DNA genomes of herpes viruses (KSHV, EBV and HSV-1) are sensed by the nuclear resident IFI16 protein, resulting in the formation of the IFI16-ASC-procaspase-1 inflammasome complex. Here, we show that BRCA1 promotes viral DNA sensing by IFI16 in the nucleus and is a constituent of the triggered IFI16-ASC-procaspase-1 inflammasome. IFI16 and BRCA1 are in complex in the nucleus and their association increases in the presence of KSHV, EBV or HSV-1 genomes, but not by the DNA damage response or vaccinia virus cytoplasmic dsDNA. The absence of BRCA1 results in abrogated IFI16-genome association, IFI16 cytoplasmic translocation, IL-1β production, IFI16 interaction with STING, IRF3 phosphorylation, pIRF3 nuclear translocation, and IFN-β induction. Taken together, these results demonstrate a crucial and novel role of BRCA1 in the innate sensing of viral DNA and subsequent induction of the inflammasome and interferon-β responses.

Vyšlo v časopise: BRCA1 Regulates IFI16 Mediated Nuclear Innate Sensing of Herpes Viral DNA and Subsequent Induction of the Innate Inflammasome and Interferon-β Responses. PLoS Pathog 11(6): e32767. doi:10.1371/journal.ppat.1005030
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005030

Souhrn

Zdroje

1. Jin T, Perry A, Jiang J, Smith P, Curry JA, Unterholzner L, Jiang Z, Horvath G, Rathinam VA, Johnstone RW, Hornung V, Latz E, Bowie AG, Fitzgerald KA, Xiao TS (2012) Structures of the HIN domain: DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor. Immunity 36 : 561–571. doi: 10.1016/j.immuni.2012.02.014 22483801

2. Kerur N, Veettil MV, Sharma-Walia N, Bottero V, Sadagopan S, Otageri P, Chandran B (2011) IFI16 acts as a nuclear pathogen sensor and induces the inflammasome during Kaposi’s sarcoma associated herpesvirus infection. Cell Host and Microbe 9 : 363–375. doi: 10.1016/j.chom.2011.04.008 21575908

3. Singh VV, Kerur N, Bottero V, Dutta S, Chakraborty S, Ansari MA, Paudel N, Chikoti L, Chandran B (2013) Kaposi’s Sarcoma-Associated Herpesvirus latency in endothelial and B Cells activates gamma interferon-inducible protein 16-mediated inflammasomes. J Virol 87 : 4417–4431. doi: 10.1128/JVI.03282-12 23388709

4. Ansari MA, Singh VV, Dutta S, ValiaVettil M, Dutta D, Chikoti L, Lu J, Everly D, Chandran B (2013) Constitutive interferon-inducible protein 16-inflammasome activation during Epstein-Barr virus latency I, II, and III in B and epithelial cells. J Virol 87 : 8606–9623. doi: 10.1128/JVI.00805-13 23720728

5. Johnson KE, Chikoti L, Chandran B (2013) Herpes Simplex Virus 1 infection induces activation and subsequent inhibition of the IFI16 and NLRP3 inflammasomes. J Virol 87 : 5005–5018. doi: 10.1128/JVI.00082-13 23427152

6. Unterholner L, Keating SE, Baran M, Horan KA, Jensen SB, Sharma S, Sirosis CM, Jin T, Latz E, Xio TS, Fitzgerald KA, Paludan SR, Bowie AG (2010) IFI16 is an innate immune sensor for intracellular DNA. Nat Immunol 11 : 997–1004. doi: 10.1038/ni.1932 20890285

7. Orzalli MH, DeLuca NA, Knipe DM (2012) Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein. Proc Natl Acad Sci USA 109: E3008–17. doi: 10.1073/pnas.1211302109 23027953

8. Orzalli MH, Conwell SE, Berrios C, DeCaprio JA, Knipe DM (2013) Nuclearinterferon-inducible protein 16 promotes silencing of herpesviral and transfected DNA. Proc Natl Acad Sci USA 110: E4492–4501. doi: 10.1073/pnas.1316194110 24198334

9. Johnson KE, Bottero V, Flaherty S, Dutta S, Singh VV, Chandran B (2014) IFI16 Restricts HSV-1 Replication by Accumulating on the HSV-1 Genome, Repressing HSV-1 Gene Expression, and Directly or Indirectly Modulating Histone Modifications. PloS Pathog 10: e1004503. doi: 10.1371/journal.ppat.1004503 25375629

10. Gunther T, Grundhoff A (2010) The epigenetic landscape of Kaposi sarcoma-associated herpesvirus genomes. PloS Pathog 6: e1000935. doi: 10.1371/journal.ppat.1000935 20532208

11. Knipe DM, Lieberman PM, Jung JU, McBride AA, Morris KV, Ott M, Margolis D, Nieto A, Nevels M, Parks RJ, Kristie TM (2013) Snapshots: chromatin control of viral infection. Virology 435(1):141–156. doi: 10.1016/j.virol.2012.09.023 23217624

12. Lieberman PM (2013) Keeping it quiet: chromatin control of gamma herpesvirus latency. Nat Rev Microbiol 11(12): 863–875. doi: 10.1038/nrmicro3135 24192651

13. Turnell AS, Grand RJ (2012) DNA viruses and the cellular DNA-damage response. J Gen Virol 93 : 2076–2097. doi: 10.1099/vir.0.044412-0 22855786

14. Singh VV, Dutta D, Ansari MA, Dutta S, Chandran B (2014) Kaposi’s Sarcoma-Associated Herpesvirus induces the ATM and H2AX DNA damage response early during de novo infection of primary endothelial cells, which play roles in latency establishment. J Virol 88 : 2821–2834. doi: 10.1128/JVI.03126-13 24352470

15. Aglipay JA, Lee SW, Okada S, Fujiuchi N, Ohtsuka T, Kwak JC, Wang Y, Johnstone RW, Deng C, Qin J, Ouchi T (2003) A member of the Pyrin family, IFI16, is a novel BRCA1-associated protein involved in the p53-mediated apoptosis pathway. Oncogene 22 : 8931–8938. 14654789

16. Jakobsen MR, Paludan SR (2014) IFI16: At the interphase between innate DNA sensing and genome regulation. Cytokine Growth Factor Rev 25 : 649–655. doi: 10.1016/j.cytogfr.2014.06.004 25027602

17. Brazda V, Coufal J, Liao JC, Arrowsmith CH (2012) Preferential binding of IFI16 protein to cruciform structure and superhelical DNA. Biophys Res Commun 422 : 716–720.

18. Ouchi M, Ouchi T (2008) Role of IFI16 in DNA damage and checkpoint. Front Biosci 13 : 236–239. 17981541

19. Wang Y1, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (2000) BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 14(8): 927–939. 10783165

20. Ruffner H, Joazeiro CA, Hemmati D, Hunter T, Verma IM (2001) Cancer-predisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. Proc Natl Acad Sci USA 98 (9): 5134–5139. 11320250

21. Kliszczak AE, Rainey MD, Harhen B, Boisvert FM, Santocanale C (2011) DNA mediated chromatin pull-down for the study of chromatin replication. Sci Rep 1 : 95, doi: 10.1038/srep00095 22355613

22. Chatziniklaou G, Karakasilioti I, andGarinis GA (2014) DNA damage and innate immunity: links and trade-offs. Trends Immunol 35 : 429–435. doi: 10.1016/j.it.2014.06.003 25023467

23. Hsu LC, Ali SR, McGillivray S, Tseng PH, Mariathasan S, Humke EW, Eckmann L, Powell JJ, Nizet V, Dixit VM, Karin M (2008) A NOD2‑NALP1 complex mediates caspase-1‑dependent IL‑1β secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci USA 105 : 7803–7808. doi: 10.1073/pnas.0802726105 18511561

24. Kofoed EM, Vance RE (2011) Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477 : 592–595. doi: 10.1038/nature10394 21874021

25. Shenoy AR, Wellington DA, Kumar P, Kassa H, Booth CJ, Cresswell P, MacMicking JD (2012) GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals. Science 336 : 481–485. doi: 10.1126/science.1217141 22461501

26. Fernandes-Alnemri T, Yu JW, Datta P, Wu J, and Alnemri ES (2009) AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458 : 509–513. doi: 10.1038/nature07710 19158676

27. Morrone SR, Wang T, Constantoulakis LM, Hooy RM, Delannoy MJ, Sohn J (2014) Cooperative assembly of IFI16 filaments on dsDNA provides insights into host defense strategy. Proc Natl Acad Sci USA 111: E62–E71. doi: 10.1073/pnas.1313577111 24367117

28. Kato M, Onishi Y, Wada-Kiyama Y, Abe T, Ikemura T, Kogan S, Bolshoy A, Trifonov EN, Kiyama R (2003) Dinucleosome DNA of human K562 cells: experimental and computational characterizations. J Mol Biol 332 : 111–125. 12946351

29. Pal M, Ponticelli AS, Luse DS (2005) The role of the transcription bubble and TFIIB in promoter clearance by RNA polymerase II. Mol Cell 19 : 101–110. 15989968

30. Sun C, Schattgen SA, Pisitkun JP, Hilterbrand AT, Wang LJ, West JA, Hansen K, Horan KA, Jacobsen MR, O’Hare P, Adler H, Sun R, Ploegh HL, Damania B, Upton JW, Fitzgerald KA, Paludan SR (2015) Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection. J Immunol 194 : 1819–1831. doi: 10.4049/jimmunol.1402495 25595793

31. Sun L, Wu J, Du F, Chen X, Chen ZJ (2013) Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates type I interferon pathway. Science 339 : 786–791. doi: 10.1126/science.1232458 23258413

32. Orzalli MH, Broekema NM, Diner BA, Hancks DC, Elde NC, Cristea IM, Knipe DM (2015) cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection. Proc Natl Acad Sci USA E1773–E1781.

33. Horan KA, Hansen K, Jacobsen MR, Holm CK, Søby S, Unterholzner L, Thompson M, West JA, Iversen MB, Rasmussen SB, Ellermann-Eriksen S, Kurt-Jones E, Landolfo S, Damania B, Melchjorsen J, Bowie AG, Fitzgerald KA, Paludan SR (2013) Proteasomal degradation of herpes simplex virus capsids in macrophages releases DNA to the cytosol for recognition by DNA sensors. J Immunol 190(5): 2311–2319. doi: 10.4049/jimmunol.1202749 23345332

34. Eliezer D (2003) Folding pyrin into the family. Structure 11 : 1190–1191. 14527383

35. Vajjhala PR, Kaiser S, Smith SJ, Ong Q, Soh SL, Stacey KJ, Hill JM (2014) Identification of multifaceted binding modes for Pyrin and ASC Pyrin domains gives insights into Pyrin inflammasome assembly. J Biol Chem 289 : 23504–23519. doi: 10.1074/jbc.M114.553305 25006247

36. Li T, Diner BA, Chen J, Cristea IM (2012) Acetylation modulates cellular distribution and DNA sensing ability of interferon-inducible protein IFI16. Proc Natl Acad Sci USA 109 : 10558–10563. doi: 10.1073/pnas.1203447109 22691496

37. Henderson BR (2012) The BRCA1 breast cancer suppressor: regulation of transport, dynamics, and function at multiple subcellular locations. Scientifica (Cairo) 2012 : 796808.

38. Vance RE, Isberg RR, Portnoy DA (2009) Patterns of pathogenesis: discrimination of pathogenic and non-pathogenic microbes by innate immune system. Cell Host Microbe 6 : 10–21. doi: 10.1016/j.chom.2009.06.007 19616762

39. Fontana MF, Vance RE (2011) Two signal models in innate immunity. Immunol. Rev 243 : 26–39. doi: 10.1111/j.1600-065X.2011.01037.x 21884165

40. Blander JM, Sander LE (2012) Beyond pattern recognition: five immune checkpoints for scaling the microbial threat. Nature Rev Immunol 12 : 215–225.

41. Tomlinson GE, Chen TT, Stastny VA, Virmani AK, Spillman MA, Tonk V, Blum JL, Schneider NR, Wistuba II, Shay JW, Minna JD, Gazdar AF (1998) Characterization of a breast cancer cell line derived from a germ-line BRCA1 mutation carrier. Cancer Res 58 : 3237–3242. 9699648

42. Tiscornia G, Singer O, Verma IM (2006) Production and purification of lentiviral vectors. Nat Protoc 1 : 241–245. 17406239