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The nuclear localization signal-mediated nuclear targeting of herpes simplex virus 1 early protein UL2 is important for efficient viral production.
Aging (Albany NY). 2020 02 07; 12(3):2921-2938.A

Abstract

Herpes simplex virus 1 (HSV-1) is a representative alphaherpesvirus that can provoke a series of severe diseases to human being, but its exact pathogenesis is not perfectly understood. UL2, a uracil-DNA glycosylase involved in the process of HSV-1 DNA replication, has been shown to be predominantly targeted to the nuclei in our previous study, yet little is established regarding the subcellular localization signal or its related function of UL2 during HSV-1 propagation. Here, by creating a number of UL2 variants merged with enhanced yellow fluorescent protein, an authentic nuclear localization signal (NLS) of UL2 was, for the first time, identified and profiled to amino acids (aa) 1 to 17 (MKRACSRSPSPRRRPSS), and 12RRR14 was indispensable for its nuclear accumulation. Besides, the predicted nuclear export signal (aa 225 to 240) of UL2 was determined to be nonfunctional. Based on the HSV-1 bacterial artificial chromosome and homologous recombination technique, three recombinant viruses with mutations of the identified NLS, deletion and revertant of UL2 were constructed to assess the effect of UL2 nuclear targeting on HSV-1 replication. Compared to the wild type HSV-1, UL2 deletion remarkably restrained viral production, and mutation of NLS targeting UL2 to cytoplasm (pan-cellular distribution) in recombinant virus-infected cells showed a certain degree of deficiency in HSV-1 proliferation. Moreover, recombinant virus with UL2 deletion exhibited serious damages of viral DNA synthesis and mRNA expression, and these processes were partially disrupted in the recombinant virus with UL2 NLS mutation. Collectively, we had established a functional NLS in UL2 and showed that the NLS-mediated nuclear translocation of UL2 was important for efficient production of HSV-1. These data were of significance for further clarifying the biological function of UL2 during HSV-1 infection.

Authors+Show Affiliations

Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 510260, Guangdong, China.Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 510260, Guangdong, China.Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 510260, Guangdong, China.Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 510260, Guangdong, China.Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 510260, Guangdong, China.Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 510260, Guangdong, China.Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 510260, Guangdong, China.Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 510260, Guangdong, China.Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 510260, Guangdong, China.Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 510260, Guangdong, China.Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 510260, Guangdong, China.Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 510260, Guangdong, China.Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 510260, Guangdong, China.State Key Laboratory of Respiratory Diseases, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Panyu, Guangzhou 511436, Guangdong, China. South China Vaccine Corporation Limited, Guangzhou Science Park, Guangzhou 510663, Guangdong, China.Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 510260, Guangdong, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32035424

Citation

Li, Meili, et al. "The Nuclear Localization Signal-mediated Nuclear Targeting of Herpes Simplex Virus 1 Early Protein UL2 Is Important for Efficient Viral Production." Aging, vol. 12, no. 3, 2020, pp. 2921-2938.
Li M, Zou X, Wang Y, et al. The nuclear localization signal-mediated nuclear targeting of herpes simplex virus 1 early protein UL2 is important for efficient viral production. Aging (Albany NY). 2020;12(3):2921-2938.
Li, M., Zou, X., Wang, Y., Xu, Z., Ou, X., Li, Y., Liu, D., Guo, Y., Deng, Y., Jiang, S., Li, T., Shi, S., Bao, Y., Peng, T., & Cai, M. (2020). The nuclear localization signal-mediated nuclear targeting of herpes simplex virus 1 early protein UL2 is important for efficient viral production. Aging, 12(3), 2921-2938. https://doi.org/10.18632/aging.102786
Li M, et al. The Nuclear Localization Signal-mediated Nuclear Targeting of Herpes Simplex Virus 1 Early Protein UL2 Is Important for Efficient Viral Production. Aging (Albany NY). 2020 02 7;12(3):2921-2938. PubMed PMID: 32035424.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The nuclear localization signal-mediated nuclear targeting of herpes simplex virus 1 early protein UL2 is important for efficient viral production. AU - Li,Meili, AU - Zou,Xingmei, AU - Wang,Yuanfang, AU - Xu,Zuo, AU - Ou,Xiaowen, AU - Li,Yiwen, AU - Liu,Delong, AU - Guo,Yingjie, AU - Deng,Yangxi, AU - Jiang,Si, AU - Li,Tong, AU - Shi,Shaoxuan, AU - Bao,Yilong, AU - Peng,Tao, AU - Cai,Mingsheng, Y1 - 2020/02/07/ PY - 2019/09/27/received PY - 2020/01/19/accepted PY - 2020/2/9/pubmed PY - 2020/2/9/medline PY - 2020/2/9/entrez KW - HSV-1 UL2 KW - nuclear localization signal KW - recombinant virus SP - 2921 EP - 2938 JF - Aging JO - Aging (Albany NY) VL - 12 IS - 3 N2 - Herpes simplex virus 1 (HSV-1) is a representative alphaherpesvirus that can provoke a series of severe diseases to human being, but its exact pathogenesis is not perfectly understood. UL2, a uracil-DNA glycosylase involved in the process of HSV-1 DNA replication, has been shown to be predominantly targeted to the nuclei in our previous study, yet little is established regarding the subcellular localization signal or its related function of UL2 during HSV-1 propagation. Here, by creating a number of UL2 variants merged with enhanced yellow fluorescent protein, an authentic nuclear localization signal (NLS) of UL2 was, for the first time, identified and profiled to amino acids (aa) 1 to 17 (MKRACSRSPSPRRRPSS), and 12RRR14 was indispensable for its nuclear accumulation. Besides, the predicted nuclear export signal (aa 225 to 240) of UL2 was determined to be nonfunctional. Based on the HSV-1 bacterial artificial chromosome and homologous recombination technique, three recombinant viruses with mutations of the identified NLS, deletion and revertant of UL2 were constructed to assess the effect of UL2 nuclear targeting on HSV-1 replication. Compared to the wild type HSV-1, UL2 deletion remarkably restrained viral production, and mutation of NLS targeting UL2 to cytoplasm (pan-cellular distribution) in recombinant virus-infected cells showed a certain degree of deficiency in HSV-1 proliferation. Moreover, recombinant virus with UL2 deletion exhibited serious damages of viral DNA synthesis and mRNA expression, and these processes were partially disrupted in the recombinant virus with UL2 NLS mutation. Collectively, we had established a functional NLS in UL2 and showed that the NLS-mediated nuclear translocation of UL2 was important for efficient production of HSV-1. These data were of significance for further clarifying the biological function of UL2 during HSV-1 infection. SN - 1945-4589 UR - https://www.unboundmedicine.com/medline/citation/32035424/The_nuclear_localization_signal-mediated_nuclear_targeting_of_herpes_simplex_virus_1_early_protein_UL2_is_important_for_efficient_viral_production L2 - https://www.impactaging.com/full/12/2921 DB - PRIME DP - Unbound Medicine ER -
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