The Dengue Virus Nonstructural Protein 1 (NS1) Interacts with the Putative Epigenetic Regulator DIDO1 to Promote Flavivirus Replication in Mosquito Cells

Caraballo, Gerson; Rosales, Romel; Viettri, Mercedes; Castillo, J.; Cruz, Raymundo; Ding, Siyuan; Greenberg, Harry B.; Ludert, Juan E.

doi:10.1128/jvi.00704-22

Cited by 6 publications

(6 citation statements)

References 67 publications

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“…Amongst the cellular interactors enriched in NS5 immunoprecipitations, we identified three elements of the survival of motor neuron (SMN) complex involved in the spliceosome and small nuclear ribonucleoprotein (snRNP) assembly (Gemini 2, Gemini 3 and Smn) as well as the E3 ligase HYD (ortholog of human UBR5). In mammals, the OST complex and proteasome have previously been described as proviral host factors interacting with DENV NS1 [ 10 , 31 – 33 ], NS5 was shown to hijack the snRNP and UBR5 was purified with NS5 [ 13 ], illustrating virus-host interactions that occur both in the mosquito vector and human host. Together, these data validate our experimental model to identify physiologically relevant protein-protein interactions between virus and mosquito vector.…”

Section: Resultsmentioning

confidence: 99%

“…We identified Loqs as an interactor of NS1, expressed as part of a polyprotein with other non-structural proteins flanked by non-viral UTRs, suggesting that Loqs was recruited to NS1 via protein-protein interactions. In contrast, Loqs was not identified in the interactome of NS1 expressed individually in mosquito cells [ 33 ]. Given that NS1 is an ER resident protein secreted through the secretory pathway [ 49 , 50 ] and that Loqs is a cytoplasmic protein, the interaction of Loqs with NS1 is likely to be an indirect one, mediated by other viral non-structural proteins interacting with NS1.…”

Section: Discussionmentioning

confidence: 99%

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Arbovirus-vector protein interactomics identifies Loquacious as a co-factor for dengue virus replication in Aedes mosquitoes

et al. 2022

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Efficient virus replication in Aedes vector mosquitoes is essential for the transmission of arboviral diseases such as dengue virus (DENV) in human populations. Like in vertebrates, virus-host protein-protein interactions are essential for viral replication and immune evasion in the mosquito vector. Here, 79 mosquito host proteins interacting with DENV non-structural proteins NS1 and NS5 were identified by label-free mass spectrometry, followed by a functional screening. We confirmed interactions with host factors previously observed in mammals, such as the oligosaccharyltransferase complex, and we identified protein-protein interactions that seem to be specific for mosquitoes. Among the interactors, the double-stranded RNA (dsRNA) binding protein Loquacious (Loqs), an RNA interference (RNAi) cofactor, was found to be essential for efficient replication of DENV and Zika virus (ZIKV) in mosquito cells. Loqs did not affect viral RNA stability or translation of a DENV replicon and its proviral activity was independent of its RNAi regulatory activity. Interestingly, Loqs colocalized with DENV dsRNA replication intermediates in infected cells and directly interacted with high affinity with DENV RNA in the 3’ untranslated region in vitro (KD = 48–62 nM). Our study provides an interactome for DENV NS1 and NS5 and identifies Loqs as a key proviral host factor in mosquitoes. We propose that DENV hijacks a factor of the RNAi mechanism for replication of its own RNA.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Arbovirus-vector protein interactomics identifies Loquacious as a co-factor for dengue virus replication in Aedes mosquitoes

et al. 2022

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“…Their localization helps to enhance DENV replication [ 29 , 30 ]. C DENV NS1 interacts with DIDO1, a master epigenetic regulator and somehow elevates DENV replication [ 35 ]. D Capsid protein interacts with core histones (H2A, H2B, H3, and H4) and localizes them in cytoplasm to participate in DENV replication and propagation [ 36 ] …”

Section: Denv and The Host Epigenetic Machinerymentioning

confidence: 99%

“…Localization studies have shown that NS1 binds with the epigenetic regulator DIDO1 (Death Inducer Obligator 1) to promote virus replication, as shown in Fig. 3 C. The silencing of DIDO1 results in reduced virus replication, indicating its significant role [ 35 ]. The dengue structural protein capsid is found to localize in the nucleus and target the four core histones, H2A, H2B, H3, and H4.…”

Section: Denv and The Host Epigenetic Machinerymentioning

confidence: 99%

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Dengue virus pathogenesis and host molecular machineries

Sinha,

Singh,

Ravi Kumar

et al. 2024

J Biomed Sci

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Dengue viruses (DENV) are positive-stranded RNA viruses belonging to the Flaviviridae family. DENV is the causative agent of dengue, the most rapidly spreading viral disease transmitted by mosquitoes. Each year, millions of people contract the virus through bites from infected female mosquitoes of the Aedes species. In the majority of individuals, the infection is asymptomatic, and the immune system successfully manages to control virus replication within a few days. Symptomatic individuals may present with a mild fever (Dengue fever or DF) that may or may not progress to a more critical disease termed Dengue hemorrhagic fever (DHF) or the fatal Dengue shock syndrome (DSS). In the absence of a universally accepted prophylactic vaccine or therapeutic drug, treatment is mostly restricted to supportive measures. Similar to many other viruses that induce acute illness, DENV has developed several ways to modulate host metabolism to create an environment conducive to genome replication and the dissemination of viral progeny. To search for new therapeutic options, understanding the underlying host-virus regulatory system involved in various biological processes of the viral life cycle is essential. This review aims to summarize the complex interaction between DENV and the host cellular machinery, comprising regulatory mechanisms at various molecular levels such as epigenetic modulation of the host genome, transcription of host genes, translation of viral and host mRNAs, post-transcriptional regulation of the host transcriptome, post-translational regulation of viral proteins, and pathways involved in protein degradation.

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Peptide-ligand conjugate based immunotherapeutic approach for targeted dismissal of non-structural protein 1 of dengue virus: A novel therapeutic solution for mild and severe dengue infections

Srivastava,

Godara,

Jena

et al. 2024

International Journal of Biological Macromolecules

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The Dengue Virus Nonstructural Protein 1 (NS1) Interacts with the Putative Epigenetic Regulator DIDO1 to Promote Flavivirus Replication in Mosquito Cells

Abstract: Dengue is the most important mosquito-borne viral disease to humans. Dengue virus NS1 is a multifunctional protein essential for replication and modulation of innate immunity.

Cited by 6 publications

References 67 publications

Arbovirus-vector protein interactomics identifies Loquacious as a co-factor for dengue virus replication in Aedes mosquitoes

Arbovirus-vector protein interactomics identifies Loquacious as a co-factor for dengue virus replication in Aedes mosquitoes

Dengue virus pathogenesis and host molecular machineries

Peptide-ligand conjugate based immunotherapeutic approach for targeted dismissal of non-structural protein 1 of dengue virus: A novel therapeutic solution for mild and severe dengue infections

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