Uncontrolled immune responses to intracellular DNA have been shown to induce autoimmune diseases. Homeostasis regulation of immune responses to cytosolic DNA is critical for limiting the risk of autoimmunity and survival of the host. Here, we report that the E3 ubiquitin ligase tripartite motif protein 30α (TRIM30α) was induced by herpes simplex virus type 1 (HSV-1) infection in dendritic cells (DCs). Knockdown or genetic ablation of TRIM30α augmented the type I IFNs and interleukin-6 response to intracellular DNA and DNA viruses. Trim30α-deficient mice were more resistant to infection by DNA viruses. Biochemical analyses showed that TRIM30α interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response. Overexpression of TRIM30α promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway. These findings indicate that E3 ligase TRIM30α is an important negative-feedback regulator of innate immune responses to DNA viruses by targeting STING.
References
[1]
Takeuchi O, Akira S (2010) Pattern Recognition Receptors and Inflammation. Cell 140: 805–820. doi: 10.1016/j.cell.2010.01.022. pmid: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. pmid:11607032 doi: 10.1038/35099560
[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. pmid:14976262 doi: 10.1126/science.1093620
[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. pmid:15208624 doi: 10.1038/ni1087
[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. doi: 10.4049/jimmunol.175.5.2851
[6]
Paludan S？ren R, Bowie Andrew G (2013) Immune Sensing of DNA. Immunity 38: 870–880. doi: 10.1016/j.immuni.2013.05.004. pmid: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. pmid:11130078 doi: 10.1038/35047123
[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. pmid: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. pmid: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. pmid: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. pmid: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. pmid: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. pmid:17618271 doi: 10.1038/nature06013
[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. pmid: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. pmid: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. pmid: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. pmid: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. pmid: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. pmid: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. pmid: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. doi: 10.1016/j.immuni.2014.01.010
[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. pmid: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. pmid: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. pmid: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. pmid: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. pmid:19433799
[27]
Burdette DL, Vance RE (2012) STING and the innate immune response to nucleic acids in the cytosol. Nature Immunology 14: 19–26. doi: 10.1038/ni.2491
[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. pmid:18836477
[29]
Barber GN (2014) STING-dependent cytosolic DNA sensing pathways. Trends Immunol 35: 88–93. doi: 10.1016/j.it.2013.10.010. pmid: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. pmid: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. pmid: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. pmid:12574336 doi: 10.4049/jimmunol.170.4.1728
