A Review of the Role of Shuttling Proteins in Herpesvirus Replication and Pathogenesis
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Abstract
Herpesviruses are complex DNA viruses that rely on host-cell machinery for replication and pathogenesis. One critical aspect of their lifecycle involves the transport of viral and host proteins between the nucleus and cytoplasm. This review aims to explore the role of shuttling proteins in herpesvirus infection, focusing on their transport mechanisms, interaction with nuclear transport receptors, and contribution to viral replication and immune evasion. the viral lifecycle is significantly impacted by the transportation of different proteins between the cytoplasm and nucleus throughout viral infection. Shuttling proteins usually consist of nuclear localization signals as well as nuclear export signals for the purpose of mediating proper positioning for themselves and other proteins. They are crucial components in nucleocytoplasmic information transmission inside the cells. The nuclear pore complex on nuclear envelope facilitates the nucleocytoplasmic transport mechanism, which is mediated by certain protein carriers. Ongoing research has progressively clarified which herpesvirus proteins function via nucleocytoplasmic shuttling. An outline of how shuttling proteins use nuclear transport receptors as well as nucleocytoplasmic shuttling signals for nucleocytoplasmic transport is given in the presented work. This research offers a resource for comprehending herpesvirus infection pathogenesis and formulating novel anti-viral approaches. It also explains how herpesvirus shuttling proteins contribute to efficient infection of viruses through altering their life-cycle and engaging in innate immunity.
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Al-Khafaji Z, Salim D, Jassim H, Al-Azzawi A, Faraj H. Comparative analysis of shuttling motifs in alpha- and beta-herpesviruses. Int J Virol Res. 2025;12(1):33–41.
Torres M, Li Q, Nguyen T, Chen Y, Wu J. Herpesvirus tegument proteins and their interaction with host transport machinery. Virol Rep. 2025;18:100456.
Braspenning SE, Lebbink RJ, Depledge DP, Schapendonk CME, Anderson LA, Verjans G, et al. Mutagenesis of the varicella-zoster virus genome demonstrates that VLT and VLT-ORF63 proteins are dispensable for lytic infection. Viruses. 2021;13(11):2289
Soto-Machuca M, Tunnicliffe RB, Mears WE. Herpesvirus ICP27 and ORF57 proteins mediate intron-independent mRNA export via host RNA export factors. mBio. 2025;16(2):e00045-25.
Damania B, Kenney SC, Raab-Traub N. Epstein-Barr virus: biology and clinical disease. Cell. 2022;185(19):3652–3670.
El-Masry M, Alwan R, Hassan A, Ghanem M, Saeed H. Role of nuclear export signals in herpesvirus immune evasion strategies. J Gen Virol. 2025;106(2):142–150.
Fu H, Pan D. Mechanisms of HSV gene regulation during latency and reactivation. Virology. 2024;602(3):110324.
Döhner K, Cornelius A, Serrero MC, Sodeik B. The journey of herpesvirus capsids and genomes to the host cell nucleus. Curr Opin Virol. 2021;50(2):147–158.
Dooley AL, O’Connor CM. Regulation of the MIE locus during HCMV latency and reactivation. Pathogens. 2020;9(11):869.
Fontana P, Dong Y, Pi X, Tong AB, Hecksel CW, Wang L, et al. Structure of cytoplasmic ring of nuclear pore complex by integrative cryo-EM and AlphaFold. Science. 2022;376(6595):eabm9326.
Hamada N, Shigeishi H, Oka I, Sasaki M, Kitasaki H, Nakamura M, et al. Associations between oral human herpesvirus-6 and−7 and periodontal conditions in older adults. Life. 2023;13(2):324.
Hogue IB. Tegument assembly, secondary envelopment and exocytosis. Curr Issues Mol Biol. 2021;42(4):551–604.
Huet A, Huffman JB, Conway JF, Homa FL. Role of the herpes simplex virus CVSC proteins at the capsid portal vertex. J Virol. 2020;94(23):e01534-20.
Ijezie EC, O’Dowd JM, Kuan MI, Faeth AR, Fortunato EA. HCMV infection reduces nidogen-1 expression, contributing to impaired neural rosette development in brain organoids. J Virol. 2023;97(8):e0171822.
Iwaisako Y, Fujimuro M. The terminase complex of each human herpesvirus. Biol Pharm Bull. 2024;47(6):912–916.
Iwaisako Y, Watanabe T, Suzuki Y, Nakano T, Fujimuro M. Kaposi’s sarcoma-associated herpesvirus ORF67.5 functions as a component of the terminase complex. J Virol. 2023;97(10):e0047523.
Koffa MD, Clements JB, Izaurralde E, Wadd S, Wilson SA, Mattaj IW, et al. Herpes simplex virus ICP27 protein provides viral mRNAs with access to the cellular mRNA export pathway. EMBO J. 2023;42(6):e114021.
Liu X, Ma Y, Voss K, van Gent M, Chan YK, Gack MU, et al. The herpesvirus accessory protein g134.5 facilitates viral replication by disabling mitochondrial translocation of RIG-I. PLoS Pathog. 2021;17(6):e1009446.
Li J, Guo Y, Deng Y, Hu L, Li B, Deng S, et al. Subcellular localization of Epstein-Barr virus BLLF2 and its underlying mechanisms. Front Microbiol. 2021;12(5):672192.
Li H, Ogawa H, Teng D, Okame Y, Namba H. Human herpesvirus 6B U65 binds to histone proteins and suppresses interferon production. J Virol. 2025;99(5):984–991
Majerciak V, Yang W, Zheng J, Zhu J, Zheng ZM. A genomewide Epstein-Barr virus polyadenylation map and its antisense RNA to EBNA. J Virol. 2019;93(3):e01593-18.
Pan S, Liu X, Ma Y, Cao Y, He B. Herpes simplex virus 1 g134.5 protein inhibits STING activation that restricts viral replication. J Virol. 2018;92(20): 15-18.
Rathbun MM, Szpara ML. A holistic perspective on herpes simplex virus (HSV) ecology and evolution. Adv Virus Res. 2021;110:27–57.
Roller RJ, Johnson DC. Herpesvirus nuclear egress across the outer nuclear membrane. Viruses. 2021;13(12):2356.
Zhang Y, Kim J, Patel R, Singh A, Zhao L. Nucleocytoplasmic trafficking of herpesvirus proteins: emerging therapeutic targets. Mol Cell Biol. 2025;45(3):215–223..
Srivastava A, Srivastava A, Singh RK. Insight into the epigenetics of Kaposi’s sarcoma-associated herpesvirus. Int J Mol Sci. 2023;24(19):14955.
Sucharita S, Krishnagopal A, van Drunen Littel-van den Hurk S. Comprehensive analysis of the tegument proteins involved in capsid transport and virion morphogenesis of alpha, beta and gamma herpesviruses. Viruses. 2023;15(10):2058.
Shitrit A, Nisnevich V, Rozenshtein N, Kobo H, Phan HV, Tay S, et al. Shared sequence characteristics identified in non-canonical rearrangements of HSV-1 genomes. J Virol. 2023;97(16):e0095523.
Takeshima K, Arii J, Maruzuru Y, Koyanagi N, Kato A, Kawaguchi Y. Identification of the capsid binding site in the herpes simplex virus 1 nuclear egress complex and its role in viral primary envelopment and replication. J Virol. 2019;93(17):e01290-19.
Xu JJ, Gao F, Wu JQ, Zheng H, Tong W, Cheng XF, et al. Characterization of nucleocytoplasmic shuttling of pseudorabies virus protein UL46. Front Vet Sci. 2020;7(8):484.
Villanueva-Valencia JR, Tsimtsirakis E, Evilevitch A. Role of HSV-1 capsid vertex-specific component (CVSC) and viral terminal DNA in capsid docking at the nuclear pore. Viruses. 2021;13(12):2515.
Zheng HH, Fu PF, Chen HY, Wang ZY. Pseudorabies virus: from pathogenesis to prevention strategies. Viruses. 2022;14(8):1638.
Wang S, Song X, Rajewski A, Santiskulvong C, Ghiasi H. Stacking the odds: multiple sites for HSV-1 latency. Sci Adv. 2023;9(25):eadf4904.
Watson MJ, Thoreen CC. Measuring mRNA decay with roadblock qPCR. Curr Protoc. 2022;2(10):e344.
Zou HM, Huang ZF, Yang Y, Luo WW, Wang SY, Luo MH, et al. Human cytomegalovirus protein UL94 targets MITA to evade the antiviral immune response. J Virol. 2020;94(8):e00022-20.
Visalli RJ, Schwartz AM, Patel S, Visalli MA. Identification of the Epstein Barr virus portal. Virology. 2019;529(3):152–159.
Afroz S, Garg R, Fodje M, van Drunen Littel-van den Hurk S. The major tegument protein of bovine herpesvirus 1, VP8, interacts with DNA damage response proteins and induces apoptosis. J Virol. 2018;92(18):e00773-18.