Interferon (IFN)-mediated innate immune response is the first line of defense against viral infections. And interferon regulatory factor 7 (IRF7) is a potent transcription factor of type I IFNs and IFN stimulated genes (ISGs) and is known as the master regulator of type I IFN-dependent immune responses. To overcome the effects of IFN responses, viruses, including Kaposi's sarcoma-associated herpesvirus (KSHV), have evolved various strategies to interfere with the IRF7 functions. We previously found that KSHV ORF45 blocks virus-induced phosphorylation and nuclear translocation of IRF7. In chapter two, I further demonstrated the underlying mechanisms by which ORF45 inhibits the phosphorylation of IRF7 by IKKe and TBK1 and found ORF45 itself is robust phosphorylated by these two kinases and inhibits IRF7 phosphorylation competitively as a decoy substrate. So that the IFN responses do not become so excessive as to harm the host, IRF7 itself is delicately regulated at the transcriptional, translational, and posttranslational levels by cellular factors. In chapter three and chapter four, I identified two novel cellular binding partners of IRF7, activating transcription factor 4 (ATF4) and tripartite motif-containing protein 28 (TRIM28). ATF4 is the critical regulator for integrated stress responses. Viral infections trigger both innate immune responses and integrated stress responses, however the link between these two pathways is less understood. I determined that ATF4 blocks IRF7 activation by inhibiting its transcription and phosphorylation, and IRF7 increases the expression and activity of ATF4 in return. This regulatory circuit between ATF4 and IRF7 suggests the cross-regulation between innate immune response and integrate stress response. Posttranslational modifications, such as phosphorylation, ubiquitination, ans SUMOylation, are critical for delicate regulation of IRF7 activation and activity. Modification of IRF7 by small ubiquitin-related modifiers (SUMO)s has been shown to regulate IFN expression and antiviral responses negatively, but the specific E3 ligase needed for IRF7 SUMOylation has remained unknown. In chapter four, I identified TRIM28 as a binding partner of IRF7. I have demonstrated that TRIM28 also interacts with the SUMO E2 enzyme and increases SUMOylation of IRF7 both in vivo and in vitro, suggesting it acts as a SUMO E3 ligase of IRF7. Unlike the common SUMO E3 ligase PIAS1, the E3 activity of TRIM28 is specific to IRF7, because it had little effect on IRF7's close relative IRF3. Therefore, so far as we know, TRIM28 is the first IRF7-specific SUMO E3 to be reported. TRIM28-mediated SUMOylation of IRF7 is increased during viral infection. SUMOylation of transcription factors usually results in transcriptional repression. Consequently, overexpression of TRIM28 inhibits IRF7 transactivation activity, whereas knockdown of TRIM28 has the opposite effect and potentiates IFN production and antiviral responses. In summary, our results suggest that TRIM28 is a specific SUMO E3 ligase and negative regulator of IRF7. / A Dissertation submitted to the Department of Biological Science in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Fall Semester, 2011. / November 1, 2011. / ATF4, innate immunity, interferon, IRF7, KSHV ORF45, TRIM28 / Includes bibliographical references. / Fanxiu Zhu, Professor Directing Dissertation; Wei Yang, University Representative; Kenneth Roux, Committee Member; Thomas C. S. Keller, III, Committee Member; Hengli Tang, Committee Member.
| Identifer | oai:union.ndltd.org:fsu.edu/oai:fsu.digital.flvc.org:fsu_182973 |
| Contributors | Liang, Qiming (authoraut), Zhu, Fanxiu (professor directing dissertation), Yang, Wei (university representative), Roux, Kenneth (committee member), Keller, Thomas C. S. (committee member), Tang, Hengli (committee member), Department of Biological Science (degree granting department), Florida State University (degree granting institution) |
| Publisher | Florida State University, Florida State University |
| Source Sets | Florida State University |
| Language | English, English |
| Detected Language | English |
| Type | Text, text |
| Format | 1 online resource, computer, application/pdf |
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