Abstract

IRF7, a members of the IFN regulatory family, when activated by viral infection or by toll-like receptor stimulation induces type I IFN transcription in many cell types, including DCs. We showed that IRF7 is conjugated to SUMO 1, 2 and 3. The SUMO modifications of IRF7 were caused by pathogen mediated activation of TLR and RIG-I pathways, causing strong inhibition of IFN transcription. Similarly, a related factor IRF3 was found SUMOylated causing similar inhibition of IFN transcription. It is likely that this SUMO modification is a mechanism to attenuate IFN induction postactivation to control excessive inflammation. Furthermore, we found that the Ebola virus VP35 strongly inhibits IFN induction in DCs by prematurely SUMOylating IRF7 and IRF3. Our analysis showed that VP35 directly interacts with IRF7 as well as the components of host SUMO modification machinery including SUMO E3 ligase PIAS1 and the E2 enzyme Ubc9. In accordance, down regulation of PIAS1 by small hairpin RNA partially alleviated VP35 repression of IFN induction.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAHD001310-23
Application #
7968580
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
23
Fiscal Year
2009
Total Cost
$760,460
Indirect Cost

  Institution

Name
Eunice Kennedy Shriver National Institute of Child Health & Human Development
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Haque, Nazmul; Ouda, Ryota; Chen, Chao et al. (2018) ZFR coordinates crosstalk between RNA decay and transcription in innate immunity. Nat Commun 9:1145
Kurotaki, Daisuke; Nakabayashi, Jun; Nishiyama, Akira et al. (2018) Transcription Factor IRF8 Governs Enhancer Landscape Dynamics in Mononuclear Phagocyte Progenitors. Cell Rep 22:2628-2641
Kamada, Rui; Yang, Wenjing; Zhang, Yubo et al. (2018) Interferon stimulation creates chromatin marks and establishes transcriptional memory. Proc Natl Acad Sci U S A 115:E9162-E9171
Kamiyama, Reikou; Yoshimi, Ryusuke; Takeno, Mitsuhiro et al. (2018) Dysfunction of TRIM21 in interferon signature of systemic lupus erythematosus. Mod Rheumatol :1-11
Wang, Joshua W; Wu, Wai Hong; Huang, Tsui-Chin et al. (2018) Roles of Fc Domain and Exudation in L2 Antibody-Mediated Protection against Human Papillomavirus. J Virol 92:
Cougnoux, Antony; Drummond, Rebecca A; Collar, Amanda L et al. (2018) Microglia activation in Niemann-Pick disease, type C1 is amendable to therapeutic intervention. Hum Mol Genet 27:2076-2089
Valanparambil, Rajesh M; Tam, Mifong; Gros, Pierre-Paul et al. (2017) IRF-8 regulates expansion of myeloid-derived suppressor cells and Foxp3+ regulatory T cells and modulates Th2 immune responses to gastrointestinal nematode infection. PLoS Pathog 13:e1006647
White, Christine L; Kessler, Patricia M; Dickerman, Benjamin K et al. (2016) Interferon Regulatory Factor 8 (IRF8) Impairs Induction of Interferon Induced with Tetratricopeptide Repeat Motif (IFIT) Gene Family Members. J Biol Chem 291:13535-45
Pan, Ji-An; Sun, Yu; Jiang, Ya-Ping et al. (2016) TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis. Mol Cell 61:720-733
Paschall, Amy V; Zhang, Ruihua; Qi, Chen-Feng et al. (2015) IFN regulatory factor 8 represses GM-CSF expression in T cells to affect myeloid cell lineage differentiation. J Immunol 194:2369-79

Showing the most recent 10 out of 53 publications