A Conserved Mechanism of APOBEC3 Relocalization by Herpesviral Ribonucleotide Reductase Large Subunits
A Conserved Mechanism of APOBEC3 Relocalization by Herpesviral Ribonucleotide Reductase Large Subunits
Abstract 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 co-immunoprecipitation and immunofluorescent microscopy approaches to ask whether this mechanism is shared with the closely related γ-herpesvirus Kaposi’s sarcoma-associated herpesvirus (KSHV) and the more distantly related α-herpesvirus, herpes simplex virus-1 (HSV-1). The large RNR subunit of KSHV, ORF61, co-precipitated 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 co-precipitated 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. These results combine to indicate that both γ- and α-herpesviruses use a conserved RNR-dependent mechanism to relocalize A3B and A3A and, further, suggest that HSV-1 possesses at least one additional mechanism to neutralize these antiviral enzymes. ImportanceThe APOBEC3 family of DNA cytosine deaminases constitutes a vital innate immune defense against a range of different viruses. A novel counter-restriction mechanism has recently been uncovered for the γ-herpesvirus 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 γ-herpesvirus, KSHV, and to a more distantly related α-herpesvirus, 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.
de Moraes Sofia N¨?brega、Attarian Claire、Yockteng-Melgar Jaime、Rice Stephen A.、Biolatti Matteo、Bierle Craig J.、Galitska Ganna、Dell?ˉOste Valentina、Cheng Adam Z.、Frappier Lori、Jarvis Matthew C.、Harris Reuben S.
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota||Masonic Cancer Center, University of Minnesota, Minneapolis||Institute for Molecular Virology, University of Minnesota||Center for Genome Engineering, University of MinnesotaDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota||Masonic Cancer Center, University of Minnesota, Minneapolis||Institute for Molecular Virology, University of Minnesota||Center for Genome Engineering, University of MinnesotaDepartment of Molecular Genetics, University of Toronto||Facultad de Ciencias de la Vida, Escuela Superior Polit¨|cnica del LitoralInstitute for Molecular Virology, University of Minnesota||Department of Microbiology and Immunology, University of MinnesotaLaboratory of Pathogenesis of Viral Infections, Department of Public Health and Pediatric Sciences, University of TurinInstitute for Molecular Virology, University of Minnesota||Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, University of MinnesotaLaboratory of Pathogenesis of Viral Infections, Department of Public Health and Pediatric Sciences, University of TurinLaboratory of Pathogenesis of Viral Infections, Department of Public Health and Pediatric Sciences, University of TurinDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota||Masonic Cancer Center, University of Minnesota, Minneapolis||Institute for Molecular Virology, University of Minnesota||Center for Genome Engineering, University of MinnesotaDepartment of Molecular Genetics, University of TorontoDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota||Masonic Cancer Center, University of Minnesota, Minneapolis||Institute for Molecular Virology, University of Minnesota||Center for Genome Engineering, University of MinnesotaDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota||Masonic Cancer Center, University of Minnesota, Minneapolis||Institute for Molecular Virology, University of Minnesota||Center for Genome Engineering, University of Minnesota||Howard Hughes Medical Institute, University of Minnesota
分子生物学基础医学生物科学研究方法、生物科学研究技术
APOBEC3AAPOBEC3Binnate antiviral immunityherpesvirusesribonucleotide reductase
de Moraes Sofia N¨?brega,Attarian Claire,Yockteng-Melgar Jaime,Rice Stephen A.,Biolatti Matteo,Bierle Craig J.,Galitska Ganna,Dell?ˉOste Valentina,Cheng Adam Z.,Frappier Lori,Jarvis Matthew C.,Harris Reuben S..A Conserved Mechanism of APOBEC3 Relocalization by Herpesviral Ribonucleotide Reductase Large Subunits[EB/OL].(2025-03-28)[2025-05-05].https://www.biorxiv.org/content/10.1101/765735.点此复制
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