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Discrete spatio-temporal regulation of tyrosine phosphorylation directs influenza A virus M1 protein towards its function in virion assembly.

ABSTRACT: Small RNA viruses only have a very limited coding capacity, thus most viral proteins have evolved to fulfill multiple functions. The highly conserved matrix protein 1 (M1) of influenza A viruses is a prime example for such a multifunctional protein, as it acts as a master regulator of virus replication whose different functions have to be tightly regulated. The underlying mechanisms, however, are still incompletely understood. Increasing evidence points towards an involvement of posttranslational modifications in the spatio-temporal regulation of M1 functions. Here, we analyzed the role of M1 tyrosine phosphorylation in genuine infection by using recombinant viruses expressing M1 phosphomutants. Presence of M1 Y132A led to significantly decreased viral replication compared to wildtype and M1 Y10F. Characterization of phosphorylation dynamics by mass spectrometry revealed the presence of Y132 phosphorylation in M1 incorporated into virions that is most likely mediated by membrane-associated Janus kinases late upon infection. Molecular dynamics simulations unraveled a potential phosphorylation-induced exposure of the positively charged linker domain between helices 4 and 5, supposably acting as interaction platform during viral assembly. Consistently, M1 Y132A showed a defect in lipid raft localization due to reduced interaction with viral HA protein resulting in a diminished structural stability of viral progeny and the formation of filamentous particles. Importantly, reduced M1-RNA binding affinity resulted in an inefficient viral genome incorporation and the production of non-infectious virions that interferes with virus pathogenicity in mice. This study advances our understanding of the importance of dynamic phosphorylation as a so far underestimated level of regulation of multifunctional viral proteins and emphasizes the potential feasibility of targeting posttranslational modifications of M1 as a novel antiviral intervention.

SUBMITTER: Mecate-Zambrano A

PROVIDER: S-EPMC7485975 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Discrete spatio-temporal regulation of tyrosine phosphorylation directs influenza A virus M1 protein towards its function in virion assembly.

Mecate-Zambrano Angeles A Sukumar Swathi S Seebohm Guiscard G Ciminski Kevin K Schreiber André A Anhlan Darisuren D Greune Lilo L Wixler Ludmilla L Grothe Stephanie S Stein Nora Caroline NC Schmidt M Alexander MA Langer Klaus K Schwemmle Martin M Shi Tianlai T Ludwig Stephan S Boergeling Yvonne Y

PLoS pathogens 20200831 8

Small RNA viruses only have a very limited coding capacity, thus most viral proteins have evolved to fulfill multiple functions. The highly conserved matrix protein 1 (M1) of influenza A viruses is a prime example for such a multifunctional protein, as it acts as a master regulator of virus replication whose different functions have to be tightly regulated. The underlying mechanisms, however, are still incompletely understood. Increasing evidence points towards an involvement of posttranslationa ...[more]

PMID: 32866218

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Project description:BACKGROUND: Culicoides imicola KIEFFER, 1913 (Diptera: Ceratopogonidae) is the principal vector of Bluetongue disease in the Mediterranean basin, Africa and Asia. Previous studies have identified a range of eco-climatic variables associated with the distribution of C. imicola, and these relationships have been used to predict the large-scale distribution of the vector. However, these studies are not temporally-explicit and can not be used to predict the seasonality in C. imicola abundances. Between 2001 and 2006, longitudinal entomological surveillance was carried out throughout Italy, and provided a comprehensive spatio-temporal dataset of C. imicola catches in Onderstepoort-type black-light traps, in particular in Sardinia where the species is considered endemic. METHODS: We built a dynamic model that allows describing the effect of eco-climatic indicators on the monthly abundances of C. imicola in Sardinia. Model precision and accuracy were evaluated according to the influence of process and observation errors. RESULTS: A first-order autoregressive cofactor, a digital elevation model and MODIS Land Surface Temperature (LST)/or temperatures acquired from weather stations explained ~77% of the variability encountered in the samplings carried out in 9 sites during 6?years. Incorporating Normalized Difference Vegetation Index (NDVI) or rainfall did not increase the model's predictive capacity. On average, dynamics simulations showed good accuracy (predicted vs. observed r corr?=?0.9). Although the model did not always reproduce the absolute levels of monthly abundances peaks, it succeeded in reproducing the seasonality in population level and allowed identifying the periods of low abundances and with no apparent activity. On that basis, we mapped C. imicola monthly distribution over the entire Sardinian region. CONCLUSIONS: This study demonstrated prospects for modelling data arising from Culicoides longitudinal entomological surveillance. The framework explicitly incorporates the influence of eco-climatic factors on population growth rates and accounts for observation and process errors. Upon validation, such a model could be used to predict monthly population abundances on the basis of environmental conditions, and hence can potentially reduce the amount of entomological surveillance.

Project description:With the incessant challenge of exposure to the air we breathe, lung tissue suffers the highest levels of oxygen tension and thus requires robust antioxidant defenses. Furthermore, following injury or infection, lung tissue faces the additional challenge of inflammation-induced reactive oxygen and nitrogen species (ROS/RNS). Little is known about the identity or distribution of lung antioxidant enzymes under normal conditions or during infection-induced inflammation. Using a mouse model of influenza (H1N1 influenza virus A/PR/8/34 [PR8]) in combination with bioinformatics, we identified seven lung-abundant antioxidant enzymes: Glutathione peroxidase 3 (Gpx3), Superoxide dismutase 3 (Sod3), Transferrin (Tf), peroxyredoxin6 (Prdx6), glutathione S-transferase kappa 1 (Gstk1), Catalase (Cat), and Glutathione peroxidase 8 (Gpx8). Interestingly, despite the demand for antioxidants during inflammation, influenza caused depletion in two key antioxidants: Cat and Prdx6. As Cat is highly expressed in Clara cells, virus-induced Clara cell loss contributes to the depletion in Cat. Prdx6 is also reduced due to Clara cell loss, however there is a coincident increase in Prdx6 levels in the alveoli, resulting in only a subtle reduction of Prdx6 overall. Analogously, Gpx3 shifts from the basement membranes underlying the bronchioles and blood vessels to the alveoli, thus maintaining balanced expression. Taken together, these studies identify key lung antioxidants and reveal their distribution among specific cell types. Furthermore, results show that influenza depletes key antioxidants, and that in some cases there is coincident increased expression, consistent with compensatory expression. Given that oxidative stress is known to be a key risk factor during influenza infection, knowledge about the antioxidant repertoire of lungs, and the spatio-temporal distribution of antioxidants, contributes to our understanding of the underlying mechanisms of influenza-induced morbidity and mortality.

Dataset Information

Discrete spatio-temporal regulation of tyrosine phosphorylation directs influenza A virus M1 protein towards its function in virion assembly.

Publications

Discrete spatio-temporal regulation of tyrosine phosphorylation directs influenza A virus M1 protein towards its function in virion assembly.

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