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1.
J Virol ; 93(10)2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30842328

RESUMO

SUMOylation is a posttranslational modification that has crucial roles in diverse cellular biological pathways and in various viral life cycles. In this study, we found that the VP1 protein, the RNA-dependent RNA polymerase of avibirnavirus infectious bursal disease virus (IBDV), regulates virus replication by SUMOylation during infection. Our data demonstrated that the polymerase VP1 is efficiently modified by small ubiquitin-like modifier 1 (SUMO1) in avibirnavirus-infected cell lines. Mutation analysis showed that residues 404I and 406I within SUMO interaction motif 3 of VP1 constitute the critical site for SUMO1 modification. Protein stability assays showed that SUMO1 modification enhanced significantly the stability of polymerase VP1 by inhibiting K48-linked ubiquitination. A reverse genetic approach showed that only IBDV with I404C/T and I406C/F mutations of VP1 could be rescued successfully with decreased replication ability. Our data demonstrated that SUMO1 modification is essential to sustain the stability of polymerase VP1 during IBDV replication and provides a potential target for designing antiviral drugs targeting IBDV.IMPORTANCE SUMOylation is an extensively discussed posttranslational modification in diverse cellular biological pathways. However, there is limited understanding about SUMOylation of viral proteins of IBDV during infection. In the present study, we revealed a SUMO1 modification of VP1 protein, the RNA-dependent RNA polymerase of avibirnavirus infectious bursal disease virus (IBDV). The required site of VP1 SUMOylation comprised residues 404I and 406I of SUMO interaction motif 3, which was essential for maintaining its stability by inhibiting K48-linked ubiquitination. We also showed that IBDV with SUMOylation-deficient VP1 had decreased replication ability. These data demonstrated that the SUMOylation of IBDV VP1 played an important role in maintaining IBDV replication.


Assuntos
Vírus da Doença Infecciosa da Bursa/metabolismo , Proteína SUMO-1/metabolismo , Proteínas Estruturais Virais/metabolismo , Avibirnavirus/metabolismo , Avibirnavirus/patogenicidade , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Vírus da Doença Infecciosa da Bursa/patogenicidade , Vírus da Doença Infecciosa da Bursa/fisiologia , Processamento de Proteína Pós-Traducional , RNA Replicase/genética , Proteína SUMO-1/fisiologia , Sumoilação , Ubiquitinação , Proteínas Virais/metabolismo , Proteínas Estruturais Virais/genética , Replicação Viral/fisiologia
2.
Sci Rep ; 5: 14794, 2015 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-26440769

RESUMO

Unlike other viral protease, Avibirnavirus infectious bursal disease virus (IBDV)-encoded viral protease VP4 forms unusual intracellular tubule-like structures during viral infection. However, the formation mechanism and potential biological functions of intracellular VP4 tubules remain largely elusive. Here, we show that VP4 can assemble into tubules in diverse IBDV-infected cells. Dynamic analysis show that VP4 initiates the assembly at early stage of IBDV infection, and gradually assembles into larger size of fibrils within the cytoplasm and nucleus. Intracellular assembly of VP4 doesn't involve the host cytoskeleton, other IBDV-encoded viral proteins or vital subcellular organelles. Interestingly, the last C-terminal hydrophobic and amyloidogenic stretch (238)YHLAMA(243) with two "aggregation-prone" alanine residues was found to be essential for its intracellular self-assembly. The assembled VP4 fibrils show significantly low solubility, subsequently, the deposition of highly assembled VP4 structures ultimately deformed the host cytoskeleton and nucleus, which was potentially associated with IBDV lytic infection. Importantly, the assembly of VP4 significantly reduced the cytotoxicity of protease activity in host cells which potentially prevent the premature cell death and facilitate viral replication. This study provides novel insights into the formation mechanism and biological functions of the Avibirnavirus protease-related fibrils.


Assuntos
Avibirnavirus/metabolismo , Interações Hospedeiro-Patógeno , Serina Endopeptidases/metabolismo , Proteínas Virais/metabolismo , Proteínas Estruturais Virais/metabolismo , Proteínas Amiloidogênicas/química , Proteínas Amiloidogênicas/metabolismo , Animais , Avibirnavirus/patogenicidade , Embrião de Galinha , Chlorocebus aethiops , Citoesqueleto/metabolismo , Células HEK293/virologia , Humanos , Vírus da Doença Infecciosa da Bursa/metabolismo , Vírus da Doença Infecciosa da Bursa/patogenicidade , Peptídeos/química , Peptídeos/metabolismo , Serina Endopeptidases/química , Solubilidade , Células Vero/virologia , Proteínas Virais/química , Proteínas Estruturais Virais/química
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