TRIM30α Is a Negative-Feedback Regulator of the Intracellular DNA and DNA Virus-Triggered Response by Targeting STING

English version České info

Negative-feedback regulation is a broad and pivotal biological event to maintain the homeostasis of the host. Viral DNA species derived from DNA viruses or retroviruses can activate STING signaling to produce pro-inflammatory cytokines and type I interferon, which further recruit immune cells or induce interferon stimulated genes (ISGs) to clear viral infection respectively. However, excessive STING-signaling activation has been shown to induce autoimmune disorders. Thus, it is important to finely turn off STING signaling. Here we demonstrate that TRIM30α is rapidly induced followed by STING activation. Trim30α-deficient mice show more resistance to infection by DNA viruses. Meanwhile, knockdown or genetic ablation of TRIM30α augments the type I IFNs and IL-6 responses to intracellular DNA and DNA viruses. Biochemical analyses show that TRIM30α interacts with STING and promotes the degradation of STING via K48-linked ubiquitination at Lys275. These findings demonstrate that induced TRIM30α is a negative-feedback regulator of STING pathway activation triggered by DNA and DNA viruses, which helps the host to avoid excessive response and maintain homeostasis.

Vyšlo v časopise: TRIM30α Is a Negative-Feedback Regulator of the Intracellular DNA and DNA Virus-Triggered Response by Targeting STING. PLoS Pathog 11(6): e32767. doi:10.1371/journal.ppat.1005012
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005012

Souhrn

Zdroje

1. Takeuchi O, Akira S (2010) Pattern Recognition Receptors and Inflammation. Cell 140: 805–820. doi: 10.1016/j.cell.2010.01.022 20303872

2. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappa B by Toll-like receptor 3. Nature 413: 732–738. 11607032

3. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, et al. (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303: 1526–1529. 14976262

4. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, et al. (2004) The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nature Immunology 5: 730–737. 15208624

5. Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, et al. (2005) Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. Journal of Immunology 175: 2851–2858.

6. Paludan Søren R, Bowie Andrew G (2013) Immune Sensing of DNA. Immunity 38: 870–880. doi: 10.1016/j.immuni.2013.05.004 23706668

7. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, et al. (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408: 740–745. 11130078

8. Burckstummer T, Baumann C, Bluml S, Dixit E, Durnberger G, et al. (2009) An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nature Immunology 10: 266–272. doi: 10.1038/ni.1702 19158679

9. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, et al. (2009) AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458: 514–U516. doi: 10.1038/nature07725 19158675

10. Rathinam VAK, Jiang ZZ, Waggoner SN, Sharma S, Cole LE, et al. (2010) The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nature Immunology 11: 395–403. doi: 10.1038/ni.1864 20351692

11. Ablasser A, Bauernfeind F, Hartmann G, Latz E, Fitzgerald KA, et al. (2009) RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III—transcribed RNA intermediate. Nature Immunology 10: 1065–1072. doi: 10.1038/ni.1779 19609254

12. Chiu Y-H, MacMillan JB, Chen ZJ (2009) RNA Polymerase III Detects Cytosolic DNA and Induces Type I Interferons through the RIG-I Pathway. Cell 138: 576–591. doi: 10.1016/j.cell.2009.06.015 19631370

13. Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H, et al. (2007) DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448: 501–U514. 17618271

14. Zhang Z, Yuan B, Bao M, Lu N, Kim T, et al. (2011) The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat Immunol 12: 959–965. doi: 10.1038/ni.2091 21892174

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

16. Unterholzner L, Keating SE, Baran M, Horan KA, Jensen SB, et al. (2010) IFI16 is an innate immune sensor for intracellular DNA. Nature Immunology 11: 997–1004. doi: 10.1038/ni.1932 20890285

17. Stetson DB, Ko JS, Heidmann T, Medzhitov R (2008) Trex1 Prevents Cell-Intrinsic Initiation of Autoimmunity. Cell 134: 587–598. doi: 10.1016/j.cell.2008.06.032 18724932

18. Zhang Z, Bao M, Lu N, Weng L, Yuan B, et al. (2013) The E3 ubiquitin ligase TRIM21 negatively regulates the innate immune response to intracellular double-stranded DNA. Nat Immunol 14: 172–178. doi: 10.1038/ni.2492 23222971

19. Zhong B, Zhang L, Lei C, Li Y, Mao A-P, et al. (2009) The Ubiquitin Ligase RNF5 Regulates Antiviral Responses by Mediating Degradation of the Adaptor Protein MITA. Immunity 30: 397–407. doi: 10.1016/j.immuni.2009.01.008 19285439

20. Konno H, Konno K, Barber GN (2013) Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell 155: 688–698. doi: 10.1016/j.cell.2013.09.049 24119841

21. Zhang L, Mo J, Swanson Karen V, Wen H, Petrucelli A, et al. (2014) NLRC3, a Member of the NLR Family of Proteins, Is a Negative Regulator of Innate Immune Signaling Induced by the DNA Sensor STING. Immunity.

22. Shi M, Deng W, Bi E, Mao K, Ji Y, et al. (2008) TRIM30 alpha negatively regulates TLR-mediated NF-kappa B activation by targeting TAB2 and TAB3 for degradation. Nat Immunol 9: 369–377. doi: 10.1038/ni1577 18345001

23. Hu Y, Mao K, Zeng Y, Chen S, Tao Z, et al. (2010) Tripartite-motif protein 30 negatively regulates NLRP3 inflammasome activation by modulating reactive oxygen species production. J Immunol 185: 7699–7705. doi: 10.4049/jimmunol.1001099 21048113

24. Ishikawa H, Barber GN (2008) STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455: 674–678. doi: 10.1038/nature07317 18724357

25. Ishikawa H, Ma Z, Barber GN (2009) STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461: 788–792. doi: 10.1038/nature08476 19776740

26. Sun W, Li Y, Chen L, Chen H, You F, et al. (2009) ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc Natl Acad Sci U S A 106: 8653–8658. doi: 10.1073/pnas.0900850106 19433799

27. Burdette DL, Vance RE (2012) STING and the innate immune response to nucleic acids in the cytosol. Nature Immunology 14: 19–26.

28. Ozato K, Shin D-M, Chang T-H, Morse HC (2008) TRIM family proteins and their emerging roles in innate immunity. Nature Reviews Immunology 8: 849–860. doi: 10.1038/nri2413 18836477

29. Barber GN (2014) STING-dependent cytosolic DNA sensing pathways. Trends Immunol 35: 88–93. doi: 10.1016/j.it.2013.10.010 24309426

30. Wu J, Sun L, Chen X, Du F, Shi H, et al. (2013) Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339: 826–830. doi: 10.1126/science.1229963 23258412

31. Yang B, Wang J, Wang Y, Zhou H, Wu X, et al. (2013) Novel Function of Trim44 Promotes an Antiviral Response by Stabilizing VISA. The Journal of Immunology 190: 3613–3619. doi: 10.4049/jimmunol.1202507 23460740

32. Hou W, Wu Y, Sun S, Shi M, Sun Y, et al. (2003) Pertussis toxin enhances Th1 responses by stimulation of dendritic cells. J Immunol 170: 1728–1736. 12574336