KHNYN is essential for the zinc finger antiviral protein (ZAP) to restrict HIV-1 containing clustered CpG dinucleotides.

Mattia Ficarelli,Michela Mazzon,Harry Wilson,Rui Pedro Galão,Mark Marsh,Irati Antzin-Anduetza,Chad M Swanson,Stuart Jd Neil

doi:10.7554/elife.46767

Mattia Ficarelli, Michela Mazzon + Show 6 more

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https://doi.org/10.7554/elife.46767

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Abstract

CpG dinucleotides are suppressed in most vertebrate RNA viruses, including HIV-1, and introducing CpGs into RNA virus genomes inhibits their replication. The zinc finger antiviral protein (ZAP) binds regions of viral RNA containing CpGs and targets them for degradation. ZAP does not have enzymatic activity and recruits other cellular proteins to inhibit viral replication. We found that KHNYN, a protein with no previously known function, interacts with ZAP. KHNYN overexpression selectively inhibits HIV-1 containing clustered CpG dinucleotides and this requires ZAP and its cofactor TRIM25. KHNYN requires both its KH-like domain and NYN endonuclease domain for antiviral activity. Crucially, depletion of KHNYN eliminated the deleterious effect of CpG dinucleotides on HIV-1 RNA abundance and infectious virus production and also enhanced the production of murine leukemia virus. Overall, we have identified KHNYN as a novel cofactor for ZAP to target CpG-containing retroviral RNA for degradation.

Highlights

A major component of the innate immune system are cell intrinsic antiviral proteins
The abundance of CpG dinucleotides is suppressed in many vertebrate RNA virus genomes and when CpGs are experimentally introduced into picornaviruses or influenza A virus, replication is inhibited (Atkinson et al, 2014; Burns et al, 2009; Gaunt et al, 2016; Karlin et al, 1994; Tulloch et al, 2014)
KHNYN interacts with zinc finger antiviral protein (ZAP) and selectively inhibits HIV-1 containing clustered CpG dinucleotides in a ZAP- and TRIM25-dependent manner

Summary

Introduction

A major component of the innate immune system are cell intrinsic antiviral proteins. These act at multiple steps in viral replication cycles and some are induced by type I interferons (Schneider et al, 2014). The abundance of CpG dinucleotides is suppressed in many vertebrate RNA virus genomes and when CpGs are experimentally introduced into picornaviruses or influenza A virus, replication is inhibited (Atkinson et al, 2014; Burns et al, 2009; Gaunt et al, 2016; Karlin et al, 1994; Tulloch et al, 2014). This shows that CpG suppression in diverse RNA viruses is required for efficient replication

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