Publication Date

2015-03-15

Availability

Embargoed

Embargo Period

2017-03-14

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2015-01-29

First Committee Member

Edward W. Harhaj

Second Committee Member

Zhibin Chen

Third Committee Member

Wasif N. Khan

Fourth Committee Member

Enrique A. Mesri

Fifth Committee Member

Joyce M. Slingerland

Sixth Committee Member

Fanxiu Zhu

Abstract

The human T cell leukemia virus type I (HTLV-I) inhibits host antiviral signaling pathways although the underlying mechanisms are unclear. Here we found that the HTLV-I Tax oncoprotein induced the expression of SOCS1, an inhibitor of interferon signaling. Tax required NF-κB, but not CREB, to induce the expression of SOCS1 in T cells. Furthermore, Tax interacted with SOCS1 in both transfected cells and in HTLV-I transformed cell lines. Although SOCS1 is normally a short-lived protein, in the presence of Tax, the stability of SOCS1 was greatly increased. Accordingly, Tax enhanced the replication of a heterologous virus, vesicular stomatitis virus (VSV), in a SOCS1-dependent manner. Surprisingly, Tax required SOCS1 to inhibit RIG-I-dependent antiviral signaling, but not the interferon-induced JAK/STAT pathway. Inhibition of SOCS1 by RNA-mediated interference in the HTLV-I transformed cell line MT-2 resulted in increased IFN-β expression accompanied by reduced HTLV-I replication and p19Gag levels. Taken together, our results reveal that Tax inhibits RIG-I-dependent antiviral signaling, in part, by hijacking an interferon regulatory protein. The transcription factor interferon regulatory factor 7 (IRF7) is a key regulator of type I interferon and plays essential roles in restricting virus infection and spread. IRF7 activation is tightly regulated to prevent excessive inflammation and autoimmunity; however, how IRF7 is suppressed by negative regulators remains poorly understood. Here, we have identified aryl hydrocarbon receptor interacting protein (AIP) as a new binding partner of IRF7. AIP inducibly interacts with IRF7 upon virus infection and potently inhibits IRF7-induced type I IFN (IFNα/β) production. Overexpression of AIP blocks virus-induced activation of IFN, whereas knockdown of AIP by siRNA potentiates viral-activated IFN production. Consistently, AIP-deficient murine embryonic fibroblasts are highly resistant to virus infection due to increased production of IFNα/β. AIP inhibits IRF7 function by antagonizing the nuclear localization of IRF7. Together, our study identifies AIP as a novel inhibitor of IRF7 and negative regulator of innate RLR signaling.

Keywords

antiviral signaling; HTLV-1; Tax; SOCS1; IRF7; AIP

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