Retroviral adapters hijack the RNA helicase UPF1 in a CRM1/XPO1-dependent manner and reveal proviral roles of UPF1

TL;DR

This study shows how retroviruses like HTLV-1 and HIV-1 hijack a cellular protein (UPF1) to aid their replication while inhibiting a natural antiviral defense mechanism.

Contribution

The study reveals a novel proviral role of UPF1 in retroviral replication and its hijacking by viral proteins Rex and Rev.

Findings

HTLV-1 Rex and HIV-1 Rev proteins increase CRM1-UPF1 association, reducing UPF1's affinity for cellular RNA.

UPF1's nuclear retention inhibits NMD, an antiviral process.

UPF1 positively regulates HTLV-1 replication steps, including vRNA export and viral particle production.

Abstract

The hijacking of CRM1 export is an important step of the retroviral replication cycle. Here, we investigated the consequences of this hijacking for the host. During HTLV-1 infection, we identified that this hijacking by the viral protein Rex favours the association between CRM1 and the RNA helicase UPF1, leading to a decreased affinity of UPF1 for cellular RNA and its nuclear retention. As a consequence, we found that the nonsense-mediated mRNA decay (NMD), known to have an antiviral function, was inhibited. Corroborating these results, we described a similar process with Rev, the functional homolog of Rex from HIV-1. Unexpectedly, we also found that, for HTLV-1, this process is coupled with the specific loading of UPF1 onto vRNA, independently of NMD. In this latter context, UPF1 positively regulates several steps of the viral replication cycle, from the nuclear export of vRNA to the production of mature viral particles.

Graphical Abstract

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