Human cytomegalovirus mediates APOBEC3B relocalization early during infection through a ribonucleotide reductase-independent mechanism.

Autor:	Fanunza E; Department of Biochemistry and Structural Biology, University of Texas Health San Antonio , San Antonio, Texas, USA.; Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato , Cagilari, Italy., Cheng AZ; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota , Minneapolis, Minnesota, USA., Auerbach AA; Department of Biochemistry and Structural Biology, University of Texas Health San Antonio , San Antonio, Texas, USA., Stefanovska B; Department of Biochemistry and Structural Biology, University of Texas Health San Antonio , San Antonio, Texas, USA.; Howard Hughes Medical Institute, University of Texas Health San Antonio , San Antonio, Texas, USA., Moraes SN; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota , Minneapolis, Minnesota, USA., Lokensgard JR; Department of Medicine, University of Minnesota , Minneapolis, Minnesota, USA., Biolatti M; Department of Public Health and Pediatric Sciences, University of Turin , Turin, Italy., Dell'Oste V; Department of Public Health and Pediatric Sciences, University of Turin , Turin, Italy., Bierle CJ; Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, University of Minnesota , Minneapolis, Minnesota, USA., Bresnahan WA; Department of Microbiology and Immunology, University of Minnesota , Minneapolis, Minnesota, USA., Harris RS; Department of Biochemistry and Structural Biology, University of Texas Health San Antonio , San Antonio, Texas, USA.; Howard Hughes Medical Institute, University of Texas Health San Antonio , San Antonio, Texas, USA.
Jazyk:	angličtina
Zdroj:	Journal of virology [J Virol] 2023 Aug 31; Vol. 97 (8), pp. e0078123. Date of Electronic Publication: 2023 Aug 11.
DOI:	10.1128/jvi.00781-23
Abstrakt:	The APOBEC3 family of DNA cytosine deaminases comprises an important arm of the innate antiviral defense system. The gamma-herpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus and the alpha-herpesviruses herpes simplex virus (HSV)-1 and HSV-2 have evolved an efficient mechanism to avoid APOBEC3 restriction by directly binding to APOBEC3B and facilitating its exclusion from the nuclear compartment. The only viral protein required for APOBEC3B relocalization is the large subunit of the ribonucleotide reductase (RNR). Here, we ask whether this APOBEC3B relocalization mechanism is conserved with the beta-herpesvirus human cytomegalovirus (HCMV). Although HCMV infection causes APOBEC3B relocalization from the nucleus to the cytoplasm in multiple cell types, the viral RNR (UL45) is not required. APOBEC3B relocalization occurs rapidly following infection suggesting the involvement of an immediate early or early (IE/E) viral protein. In support of this possibility, genetic (IE1 mutant) and pharmacologic (cycloheximide) strategies that prevent the expression of IE/E viral proteins also block APOBEC3B relocalization. In comparison, the treatment of infected cells with phosphonoacetic acid, which interferes with viral late protein expression, still permits A3B relocalization. These results combine to indicate that the beta-herpesvirus HCMV uses an RNR-independent, yet phenotypically similar, molecular mechanism to antagonize APOBEC3B. IMPORTANCE Human cytomegalovirus (HCMV) infections can range from asymptomatic to severe, particularly in neonates and immunocompromised patients. HCMV has evolved strategies to overcome host-encoded antiviral defenses to achieve lytic viral DNA replication and dissemination and, under some conditions, latency and long-term persistence. Here, we show that HCMV infection causes the antiviral factor, APOBEC3B, to relocalize from the nuclear compartment to the cytoplasm. This overall strategy resembles that used by related herpesviruses. However, the HCMV relocalization mechanism utilizes a different viral factor(s) and available evidence suggests the involvement of at least one protein expressed at the early stages of infection. This knowledge is important because a greater understanding of this mechanism could lead to novel antiviral strategies that enable APOBEC3B to naturally restrict HCMV infection. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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