B'-protein phosphatase 2A is a functional binding partner of delta-retroviral integrase.

Goedele N Maertens

doi:10.1093/nar/gkv1347

Abstract

To establish infection, a retrovirus must insert a DNA copy of its RNA genome into host chromatin. This reaction is catalysed by the virally encoded enzyme integrase (IN) and is facilitated by viral genus-specific host factors. Herein, cellular serine/threonine protein phosphatase 2A (PP2A) is identified as a functional IN binding partner exclusive to δ-retroviruses, including human T cell lymphotropic virus type 1 and 2 (HTLV-1 and HTLV-2) and bovine leukaemia virus (BLV). PP2A is a heterotrimer composed of a scaffold, catalytic and one of any of four families of regulatory subunits, and the interaction is specific to the B′ family of the regulatory subunits. B′-PP2A and HTLV-1 IN display nuclear co-localization, and the B′ subunit stimulates concerted strand transfer activity of δ-retroviral INs in vitro. The protein–protein interaction interface maps to a patch of highly conserved residues on B′, which when mutated render B′ incapable of binding to and stimulating HTLV-1 and -2 IN strand transfer activity.

Highlights

Of the seven retroviral genera, two are known to cause severe and fatal conditions in humans
To identify specific binding partners of ␦-retroviral INs, proteins co-purifying with human T-cell lymphotropic virus type 1 (HTLV-1) or bovine leukaemia virus (BLV) IN from extracts of HEK293T cells stably expressing C-terminally Flag-tagged versions of the viral proteins were analysed by tandem mass spectrometry
Subunits of the heterotrimeric phosphatase phosphatase 2A (PP2A) co-purified with BLV IN in close to stoichiometric quantities (Figure 1) including ␣, ␥, ␦ and ⑀ isoforms of its B regulatory subunit (Supplementary Table S2)

Summary

Introduction

Of the seven retroviral genera (lenti-, ␣-, ␤-, ␥ −, ␦-, ⑀- and spumavirinae), two are known to cause severe and fatal conditions in humans. The lentiviruses human immunodeficiency virus type 1 (HIV-1) and HIV-2 are the aetiological agents of acquired immunodeficiency syndrome. The ␦-retrovirus human T-cell lymphotropic virus type 1 (HTLV-1) causes adult T cell leukaemia-lymphoma (ATL) and the neurological disorder HTLV-1 associated myelopathy/tropic spastic paraparesis (HAM/TSP). A range of inflammatory diseases, such as uveitis, infective dermatitis, arthritis and others is caused by HTLV-1 infection. 5% of HTLV-1 infected people eventually develop ATL, of whom most die within two years of symptom presentation [1]. The treatment of both the inflammatory and malignant conditions remains unsatisfactory

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