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The cellular Notch1 protein promotes KSHV reactivation in an Rta-dependent manner.

التفاصيل البيبلوغرافية
العنوان: The cellular Notch1 protein promotes KSHV reactivation in an Rta-dependent manner.
المؤلفون: DeCotiis-Mauro J; Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.; School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA., Han SM; Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.; School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA., Mello H; Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.; School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA., Goyeneche C; Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.; School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA., Marchesini-Tovar G; Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.; School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA., Jin L; Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.; School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA., Bellofatto V; Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.; School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA., Lukac DM; Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.; School of Graduate Studies, Rutgers Biomedical and Health Sciences, Health Science Campus at Newark, Rutgers University, Newark, New Jersey, USA.
المصدر: Journal of virology [J Virol] 2024 Aug 20; Vol. 98 (8), pp. e0078824. Date of Electronic Publication: 2024 Jul 08.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Society For Microbiology
Original Publication: Baltimore, American Society for Microbiology.
مواضيع طبية MeSH: Herpesvirus 8, Human*/physiology , Herpesvirus 8, Human*/metabolism , Herpesvirus 8, Human*/genetics , Virus Activation* , Trans-Activators*/metabolism , Trans-Activators*/genetics , Receptor, Notch1*/metabolism , Receptor, Notch1*/genetics , Immunoglobulin J Recombination Signal Sequence-Binding Protein*/metabolism , Immunoglobulin J Recombination Signal Sequence-Binding Protein*/genetics , Immediate-Early Proteins*/metabolism , Immediate-Early Proteins*/genetics , Virus Latency*, Humans ; Animals ; Vero Cells ; Chlorocebus aethiops ; Signal Transduction ; Transcription Factors/metabolism ; Transcription Factors/genetics ; Gene Expression Regulation, Viral ; Nuclear Proteins/metabolism ; Nuclear Proteins/genetics ; DNA-Binding Proteins
مستخلص: The cellular Notch signal transduction pathway is intimately associated with infections by Kaposi's sarcoma-associated herpesvirus (KSHV) and other gamma-herpesviruses. RBP-Jk, the cellular DNA binding component of the canonical Notch pathway, is the key Notch downstream effector protein in virus-infected and uninfected animal cells. Reactivation of KSHV from latency requires the viral lytic switch protein, Rta, to form complexes with RBP-Jk on numerous sites within the viral DNA. Constitutive Notch activity is essential for KSHV pathophysiology in models of Kaposi's sarcoma (KS) and Primary Effusion Lymphoma (PEL), and we demonstrate that Notch1 is also constitutively active in infected Vero cells. Although the KSHV genome contains >100 RBP-Jk DNA motifs, we show that none of the four isoforms of activated Notch can productively reactivate the virus from latency in a highly quantitative trans-complementing reporter virus system. Nevertheless, Notch contributed positively to reactivation because broad inhibition of Notch1-4 with gamma-secretase inhibitor (GSI) or expression of dominant negative mastermind-like1 (dnMAML1) coactivators severely reduced production of infectious KSHV from Vero cells. Reduction of KSHV production is associated with gene-specific reduction of viral transcription in both Vero and PEL cells. Specific inhibition of Notch1 by siRNA partially reduces the production of infectious KSHV, and NICD1 forms promoter-specific complexes with viral DNA during reactivation. We conclude that constitutive Notch activity is required for the robust production of infectious KSHV, and our results implicate activated Notch1 as a pro-viral member of a MAML1/RBP-Jk/DNA complex during viral reactivation.
Importance: Kaposi's sarcoma-associated herpesvirus (KSHV) manipulates the host cell oncogenic Notch signaling pathway for viral reactivation from latency and cell pathogenesis. KSHV reactivation requires that the viral protein Rta functionally interacts with RBP-Jk, the DNA-binding component of the Notch pathway, and with promoter DNA to drive transcription of productive cycle genes. We show that the Notch pathway is constitutively active during KSHV reactivation and is essential for robust production of infectious virus progeny. Inhibiting Notch during reactivation reduces the expression of specific viral genes yet does not affect the growth of the host cells. Although Notch cannot reactivate KSHV alone, the requisite expression of Rta reveals a previously unappreciated role for Notch in reactivation. We propose that activated Notch cooperates with Rta in a promoter-specific manner that is partially programmed by Rta's ability to redistribute RBP-Jk DNA binding to the virus during reactivation.
Competing Interests: The authors declare no conflict of interest.
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معلومات مُعتمدة: R21 AI117127 United States AI NIAID NIH HHS; R21 AI150230 United States AI NIAID NIH HHS; AI117127 HHS | National Institutes of Health (NIH); AI150230 HHS | National Institutes of Health (NIH)
فهرسة مساهمة: Keywords: HHV-8; KSHV; Rta; notch; protein/DNA interactions; reactivation; transactivation; virus replication
المشرفين على المادة: 0 (Rta protein, Human herpesvirus 8)
0 (Trans-Activators)
0 (Receptor, Notch1)
0 (Immunoglobulin J Recombination Signal Sequence-Binding Protein)
0 (Immediate-Early Proteins)
0 (NOTCH1 protein, human)
0 (RBPJ protein, human)
0 (Transcription Factors)
0 (MAML1 protein, human)
0 (Nuclear Proteins)
0 (DNA-Binding Proteins)
تواريخ الأحداث: Date Created: 20240708 Date Completed: 20240820 Latest Revision: 20240822
رمز التحديث: 20240822
مُعرف محوري في PubMed: PMC11334469
DOI: 10.1128/jvi.00788-24
PMID: 38975769
قاعدة البيانات: MEDLINE
الوصف
تدمد:1098-5514
DOI:10.1128/jvi.00788-24