Huntingtin-Interacting Protein 1 Promotes Vpr-Induced G2 Arrest and HIV-1 Infection in Macrophages.

Tomoyuki Murakami,Masami Takei,Yoko Aida,Nopporn Chutiwitoonchai,Ryosuke Matsuura

doi:10.3390/v13112308

Tomoyuki Murakami, Masami Takei + Show 3 more

Open Access

https://doi.org/10.3390/v13112308

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Journal: Viruses	Publication Date: Nov 19, 2021
Citations: 3	License type: CC BY 4.0

Affiliation: RIKEN, Nihon University, The University of Tokyo

Abstract

Human immunodeficiency virus type 1 (HIV-1) modulates the host cell cycle. The HIV-1 accessory protein Vpr arrests the cell cycle at the G2 phase in dividing cells, and the ability of Vpr to induce G2 arrest is well conserved among primate lentiviruses. Additionally, Vpr-mediated G2 arrest likely correlates with enhanced HIV-1 infection in monocyte-derived macrophages. Here, we screened small-interfering RNA to reveal candidates that suppress Vpr-induced G2 arrest and identified Huntingtin-interacting protein 1 (HIP1) required for efficient G2 arrest. Interestingly, HIP1 was not essential for Vpr-induced DNA double-strand breaks, which are required for activation of the DNA-damage checkpoint and G2 arrest. Furthermore, HIP1 knockdown suppressed HIV-1 infection in monocyte-derived macrophages. This study identifies HIP1 as a factor promoting Vpr-induced G2 arrest and HIV-1 infection in macrophages.

Highlights

We found that among the siRNAs, only siRNAs targeting Huntingtin-interacting protein 1 (HIP1) (#1 and #2), which is predominantly expressed in the brain and interacts with Huntingtin [44,45], inhibited Vpr-induced G2 arrest (Figure 2a)
Relative G2/M:G1 ratio b induce G2 arrest, HeLa cells were co-transfected with pME/Flag tagged-wild-type (WT) Vpr (F-Vpr)-IRES-ZsGreen1, either siRNA#2 or control siRNA, and either an siR-HIP1 expression vector or empty vector
The positions of HIP1, DCAF1, and β-actin areβactin are indicated. (b) HeLa cells were co-transfected with pME/F-Vpr-IRES-ZsGreen1 or control pME/F-IRES-ZsGreen1 indicated. (b) HeLa cells were co-transfected with pME/F-Vpr-IRES-ZsGreen1 or control pME/F-IRES-ZsGreen1 and 5 nM

Summary

Introduction

A small 15-kDa protein with multiple biological functions, including splicing regulation [1,2,3], support of virus release [4], nuclear import of the viral preintegration complex in macrophages [5,6,7], enhanced expression and processing of the envelope glycoprotein in macrophages [8,9,10], sustaining interleukin 6 expression to enhance HIV-1 replication [11], antagonism of exonuclease 1- and helicase-like transcription factor-mediated restriction in T cells through degradation of these proteins [12,13,14,15], regulation of apoptosis in both a positive and negative manner, and the induction of cell cycle arrest at the G2 phase in dividing cells [16,17,18,19,20,21]. Vpr-induced G2 arrest requires the association of Vpr with the CUL4 ubiquitin ligase in association with DDB1 and DCAF1 [24,34,35,36,37,38]

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