ADAR1 and PACT contribute to efficient translation of transcripts containing HIV-1 trans-activating response (TAR) element.

Evelyn Chukwurah,Rekha C Patel,Indhira Handy

doi:10.1042/bcj20160964

Evelyn Chukwurah, Rekha C Patel + Show 1 more

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https://doi.org/10.1042/bcj20160964

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Journal: The Biochemical journal	Publication Date: Mar 23, 2017
Citations: 15	License type: CC BY 4.0

Affiliation: University of South Carolina

Abstract

Human immunodeficiency virus type 1 (HIV-1) has evolved various measures to counter the host cell's innate antiviral response during the course of infection. Interferon (IFN)-stimulated gene products are produced following HIV-1 infection to limit viral replication, but viral proteins and RNAs counteract their effect. One such mechanism is specifically directed against the IFN-induced Protein Kinase PKR, which is centrally important to the cellular antiviral response. In the presence of viral RNAs, PKR is activated and phosphorylates the translation initiation factor eIF2α. This shuts down the synthesis of both host and viral proteins, allowing the cell to mount an effective antiviral response. PACT (protein activator of PKR) is a cellular protein activator of PKR, primarily functioning to activate PKR in response to cellular stress. Recent studies have indicated that during HIV-1 infection, PACT's normal cellular function is compromised and that PACT is unable to activate PKR. Using various reporter systems and in vitro kinase assays, we establish in this report that interactions between PACT, ADAR1 and HIV-1-encoded Tat protein diminish the activation of PKR in response to HIV-1 infection. Our results highlight an important pathway by which HIV-1 transcripts subvert the host cell's antiviral activities to enhance their translation.

Highlights

Cells infected with a virus employ a variety of mechanisms to counteract the negative impact of viral replication and promote cell survival [1]
In the absence of Tat, neither protein activator of protein kinase RNA-activated (PKR) (PACT) nor TAR RNA-binding protein (TRBP) had any effect on human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR)-driven expression (Figure 1D). These results indicate that similar to TRBP, PACT activates expression from HIV-1 LTR when integrated in the host chromosome and that this effect is dependent on the presence of the viral Tat protein
Tat when present with adenosine deaminase acting on RNA 1 (ADAR1) does not enhance ADAR1’s PKR inhibitory actions when compared with the inhibition observed with ADAR1 alone when PACT is absent. These results show that Tat, PACT and ADAR1 act in concert to inhibit PKR and suggest that an inhibitory complex formed with Tat, PACT and ADAR1 is essential for efficient PKR inhibition on trans-activation response (TAR)-containing HIV-1 mRNAs

Summary

Introduction

Cells infected with a virus employ a variety of mechanisms to counteract the negative impact of viral replication and promote cell survival [1]. Viral and cellular factors regulate ISGs to promote or limit viral replication, respectively, and this regulatory interplay between the virus and the host cell is crucial in determining the outcome of a viral infection. Retroviruses such as the human immunodeficiency virus type 1 (HIV-1) produce viral factors that interact with various cellular proteins, including ISGs. As a result, the virus subverts their antiviral properties or co-opts them from their regular cellular activities to facilitate efficient viral replication within the infected host cell [7,8]

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