An integral part of the antiviral innate immune response is the APOBEC3 family of single-stranded DNA cytosine deaminases, which inhibits virus replication through deamination-dependent and -independent activities. Viruses have evolved mechanisms to counteract these enzymes, such as HIV-1 Vif-mediated formation of a ubiquitin ligase to degrade virus-restrictive APOBEC3 enzymes. A new example is Epstein-Barr virus (EBV) ribonucleotide reductase (RNR)-mediated inhibition of cellular APOBEC3B (A3B). The large subunit of the viral RNR, BORF2, causes A3B relocalization from the nucleus to cytoplasmic bodies and thereby protects viral DNA during lytic replication. Here, we use coimmunoprecipitation and immunofluorescence microscopy approaches to ask whether this mechanism is shared with the closely related gammaherpesvirus Kaposi’s sarcoma-associated herpesvirus (KSHV) and the more distantly related alphaherpesvirus herpes simplex virus 1 (HSV-1). The large RNR subunit of KSHV, open reading frame 61 (ORF61), coprecipitated multiple APOBEC3s, including A3B and APOBEC3A (A3A). KSHV ORF61 also caused relocalization of these two enzymes to perinuclear bodies (A3B) and to oblong cytoplasmic structures (A3A). The large RNR subunit of HSV-1, ICP6, also coprecipitated A3B and A3A and was sufficient to promote the relocalization of these enzymes from nuclear to cytoplasmic compartments. HSV-1 infection caused similar relocalization phenotypes that required ICP6. However, unlike the infectivity defects previously reported for BORF2-null EBV, ICP6 mutant HSV-1 showed normal growth rates and plaque phenotypes. Combined, these results indicate that both gamma- and alphaherpesviruses use a conserved RNR-dependent mechanism to relocalize A3B and A3A and furthermore suggest that HSV-1 possesses at least one additional mechanism to neutralize these antiviral enzymes. IMPORTANCE The APOBEC3 family of DNA cytosine deaminases constitutes a vital innate immune defense against a range of different viruses. A novel counterrestriction mechanism has recently been uncovered for the gammaherpesvirus EBV, in which a subunit of the viral protein known to produce DNA building blocks (ribonucleotide reductase) causes A3B to relocalize from the nucleus to the cytosol. Here, we extend these observations with A3B to include a closely related gammaherpesvirus, KSHV, and a more distantly related alphaherpesvirus, HSV-1. These different viral ribonucleotide reductases also caused relocalization of A3A, which is 92% identical to A3B. These studies are important because they suggest a conserved mechanism of APOBEC3 evasion by large double-stranded DNA herpesviruses. Strategies to block this host-pathogen interaction may be effective for treating infections caused by these herpesviruses.
32An integral part of the antiviral innate immune response is the APOBEC3 family of single-stranded DNA 33 cytosine deaminases, which inhibits virus replication through deamination-dependent and -independent 34 activities. Viruses have evolved mechanisms to counteract these enzymes such as HIV-1 Vif-mediated 35 formation of a ubiquitin ligase to degrade virus-restrictive APOBEC3 enzymes. A new example is 36 Epstein-Barr virus (EBV) ribonucleotide reductase (RNR)-mediated inhibition of cellular APOBEC3B 37 (A3B). The large subunit of the viral RNR, BORF2, causes A3B relocalization from the nucleus to 38 cytoplasmic bodies and thereby protects viral DNA during lytic replication. Here, we use 39 co-immunoprecipitation and immunofluorescent microscopy approaches to ask whether this mechanism is 40 shared with the closely related -herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) and the 41 more distantly related α-herpesvirus, herpes simplex virus-1 (HSV-1). The large RNR subunit of KSHV, 42 ORF61, co-precipitated multiple APOBEC3s including A3B and APOBEC3A (A3A). KSHV ORF61 also 43 caused relocalization of these two enzymes to perinuclear bodies (A3B) and to oblong cytoplasmic 44 structures (A3A). The large RNR subunit of HSV-1, ICP6, also co-precipitated A3B and A3A and was 45 sufficient to promote the relocalization of these enzymes from nuclear to cytoplasmic compartments. 46 HSV-1 infection caused similar relocalization phenotypes that required ICP6. However, unlike the 47 infectivity defects previously reported for BORF2-null EBV, ICP6 mutant HSV-1 showed normal growth 48 rates and plaque phenotypes. These results combine to indicate that both and α-herpesviruses use a 49 conserved RNR-dependent mechanism to relocalize A3B and A3A and, further, suggest that HSV-1 50 possesses at least one additional mechanism to neutralize these antiviral enzymes. 51 52 Importance 53The APOBEC3 family of DNA cytosine deaminases constitutes a vital innate immune defense against a 54 range of different viruses. A novel counter-restriction mechanism has recently been uncovered for the 55 γ-herpesvirus EBV, in which a subunit of the viral protein known to produce DNA building blocks 56 (ribonucleotide reductase) causes A3B to relocalize from the nucleus to the cytosol. Here, we extend 57 these observations with A3B to include a closely related γ-herpesvirus, KSHV, and to a more distantly 58 related -herpesvirus, HSV-1. These different viral ribonucleotide reductases also caused relocalization 59 of A3A, which is 92% identical to A3B. These studies are important because they suggest a conserved 60 mechanism of APOBEC3 evasion by large double-stranded DNA herpesviruses. Strategies to block this 61 host-pathogen interaction may be effective for treating infections caused by these herpesviruses. 62 64An important arm of the innate immune response lies in the APOBEC family of single-stranded 65 DNA cytosine deaminases (1-3). Each of the seven human APOBEC3 (A3) enzymes, A3A-D and A3F-H, 66 have been implicated in the restri...
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