Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1289158 | ENA |
REPOSITORIES: ENA
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Project description:Usutu virus (USUV) is an emerging orthoflavivirus, which mainly affects birds but in rare cases can cause severe neuroinvasive disease in humans. Due to the limited size of the orthoflavivirus genome the virus relies on the host machinery for replication. In addition, it must subvert the host antiviral response for successful replication in the cell. Studying this complex network of virus-host protein interactions by proteomics approaches can provide us new insights in the replication cycle of viruses and can help us better understand the viral pathogenesis. We have previously shown that the USUV protein NS4A acts as an antagonist of the interferon response, and here we further map the host interaction partners of USUV NS4A using proximity labeling coupled to mass spectrometry. The resulting NS4A interactome revealed many host proteins involved in the autophagy pathway. We showed that both USUV infection and overexpression of USUV NS4A can induce the autophagy pathway. However, stimulation or inhibition of the autophagy pathway did not affect USUV replication in general. Therefore, we decided to look specifically at the role of the selective autophagy receptor sequestosome 1 (p62/SQSTM1), which was identified as an interaction partner of USUV NS4A. We found that p62 is involved in the degradation of USUV NS4A. Furthermore, the knockdown of p62 enhanced replication of USUV in A549 cells, which means p62 functions to restrict USUV replication. In conclusion, this study showed that USUV NS4A induced autophagy and was then targeted by p62 for degradation by the autophagic machinery, uncovering a new role of p62 in the antiviral defense against USUV.
2025-05-07 | PXD057492 | Pride
Project description:In recent years, arbovirus cases have surged dramatically due to the expanding distribution of the main arbovirus-vectors Aedes and Culex mosquitoes. Despite significant efforts to uncover Orthoflavivirus-specific host adaptation mechanisms of humans, systematic studies aiming to characterize virus–host interactions in arthropods are largely missing. The capsid protein is highly versatile, with multiple functions and subcellular localizations, making it an attractive target for studying host susceptibility, vector competence, and virus–vector adaptation. Here, we employed affinity purification coupled to mass spectrometry to systematically evaluate the ability of capsid proteins of 12 different pathogenic arboviruses spanning three genera to interact with the Ae. aegypti proteome. This extensive protein-protein interaction atlas uncovered novel host targets, implicated in diverse cellular pathways i.e. translation, apoptosis and RNA processing. To functionally characterize prioritized interacting host proteins, we systematically silenced 110 host genes in Ae. aegypti-derived cells and characterized their impact on the replication of three representative arboviruses: La Crosse virus, dengue virus and West Nile virus. This approach identified several novel host-dependency factors, including a new role for two components of the chromatin-remodeling Brahma complex. Interestingly, systematic silencing of individual Brahma BAP subunits revealed a conserved pan-orthoflavivirus role for both BAP and PBAP subcomplexes, when compared to prototypic alphaviruses. Furthermore, using a combination of biochemical and sequencing approaches, we characterized the cellular determinants of these interactions and profiled their functional consequences on the chromatin landscape. Altogether, this study provides an evidence-based repository to categorize and characterize novel arboviral capsid targets and explore arbovirus-vector interactions.
2026-02-05 | PXD064586 | Pride
Project description:Flavivirus infection is tightly connected to host lipid metabolism. Here, we performed shotgun lipidomics of cells infected with neurotropic Zika, West Nile, and tick-borne encephalitis viruses, as well as dengue and yellow fever virus. Early in infection specific lipids accumulated, e.g., neutral lipids in Zika and some lyso-phospholipids in all infections. Ceramide levels increased following infection with viruses that cause a cytopathic effect. In addition, fatty acid desaturation as well as glycerophospholipid metabolism were significantly altered. Importantly, depletion of enzymes involved in phosphatidylserine metabolism as well as phosphatidylinositol biosynthesis reduced orthoflavivirus titers and cytopathic effects while inhibition of fatty acid monounsaturation only rescued from virus-induced cell death. Interestingly, interfering with ceramide synthesis had opposing effects on virus replication and cytotoxicity depending on the targeted enzyme. Thus, lipid remodeling by orthoflaviviruses includes distinct changes but also common patterns shared by several viruses that are needed for efficient infection and replication.
2024-09-03 | GSE264306 | GEO
Project description:In recent years, arboviral infections have surged dramatically due to the geographic expansion of Aedes and Culex mosquitoes, their main vector mosquitoes. Despite significant efforts to uncover arbovirus–host interactions and viral protein effector functions in mammals, systematic studies aiming to characterize virus–vector interactions in arthropods are largely missing, and the functions and cellular targets of many arboviral proteins in mosquitoes remain elusive. Here, we applied a multi-omic approach to systematically evaluate the ability of arboviral capsids to interact with the Ae. aegypti proteome. This extensive multi-modal atlas across 12 pathogenic arboviral species spanning three viral genera revealed shared and distinct host factor specificities, uncovering species-, genus- and vector preference-specific patterns of host usage in mosquitoes. Functional phenotypic screening of 110 newly discovered host proteins across three prototypic arboviruses (La Crosse virus, dengue virus and West Nile virus) identified several novel host dependency factors, including a new role for the chromatin-remodeling Brahma complex in orthoflavivirus replication. Using a combination of biochemical and sequencing approaches, we characterized the cellular determinants of these interactions and profiled their functional consequences on the chromatin landscape. Altogether, this study provides a multi-layered repository to categorize and characterize arboviral capsid effector functions in invertebrates, providing important cues on novel mechanisms of transcriptional regulation via capsid-mediated modulation of chromatin accessibility in insects.
2026-02-05 | PXD070116 | Pride
Project description:Orthoflavivirus infections represent an increasing public health burden, with several members of the genus emerging or re-emerging globally. Despite the availability of few vaccines, no antiviral drugs are currently licensed for the treatment of orthoflavivirus infections. Several pre-clinical studies identified the non-structural protein 4B (NS4B), one of the least characterized viral proteins within the orthoflavivirus genus, as the most promising target for the development of potent direct-acting antivirals. However, its functional roles in viral replication are still elusive. Here, we employ an integrated proteomic approach to systematically identify cellular targets of NS4B across eight prototypic orthoflaviviruses and characterize their influence on the human proteome. Using this approach, we mapped high-confidence NS4B-interacting human proteins across the genus, underlying potentially divergent mechanisms of host adaptation across orthoflaviviruses spanning diverse pathologies and vector preferences. Among these, we unveil a novel function for UBA5, the E1-activating enzyme of the UFMylation pathway, in orthoflavivirus replication. Mechanistically, we map associations of distinct viral proteins with multiple members of the UFMylation pathway, which are selectively recruited to sites of viral replication to promote mitochondrial respiration. Finally, we demonstrate that pharmacological inhibition of UFMylation exerts potent antiviral activity in vitro and in vivo. This integrative study provides a rational framework for a system-level understanding of orthoflavivirus NS4B effector functions and sheds light on a conserved and unconventional role for UFMylation in orthoflavivirus replication.
2026-03-10 | PXD063343 | Pride
Project description:Orthoflavivirus infections represent an increasing public health burden, with several members of the genus emerging or re-emerging globally. Despite the availability of few vaccines, no antiviral drugs are currently licensed for the treatment of orthoflavivirus infections. Several pre-clinical studies identified the non-structural protein 4B (NS4B), one of the least characterized viral proteins within the orthoflavivirus genus, as the most promising target for the development of potent direct-acting antivirals. However, its functional roles in viral replication are still elusive. Here, we employ an integrated proteomic approach to systematically identify cellular targets of NS4B across eight prototypic orthoflaviviruses and characterize their influence on the human proteome. Using this approach, we mapped high-confidence NS4B-interacting human proteins across the genus, underlying potentially divergent mechanisms of host adaptation across orthoflaviviruses spanning diverse pathologies and vector preferences. Among these, we unveil a novel function for UBA5, the E1-activating enzyme of the UFMylation pathway, in orthoflavivirus replication. Mechanistically, we map associations of distinct viral proteins with multiple members of the UFMylation pathway, which are selectively recruited to sites of viral replication to promote mitochondrial respiration. Finally, we demonstrate that pharmacological inhibition of UFMylation exerts potent antiviral activity in vitro and in vivo. This integrative study provides a rational framework for a system-level understanding of orthoflavivirus NS4B effector functions and sheds light on a conserved and unconventional role for UFMylation in orthoflavivirus replication.
2026-03-10 | PXD063404 | Pride
Project description:Orthoflavivirus denguei Genome sequencing
| PRJNA1348690 | ENA