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Solving the m04 paradox: Evasion of missing-self recognition and CD8 killing by MAT uORF

Full title: Solving the m04 paradox: Evasion of missing-self recognition and CD8 klling by MAT uORF

Grantors: Deutsche Forschungsgemeinschaft

Grant number: 421448608

Grantors web site: https://www.dfg.de/

Duration: 2019 – 2022

Coordinators:
Prof.Dr. Stipan Jonjić,
Dr. Vanda Juranić Lisnić

Total funding: EUR 249.900,00

Description:
“Cytomegaloviruses (CMVs) possess multiple mechanisms to down-regulate the expression of MHC-I from the cell surface of infected cells. While this allows efficient evasion of CD8 T cell recognition, it renders infected cells sensitive to NK cell-mediated attack according the missing-self hypothesis. How CMVs simultaneously avoid these two defense systems remains largely unclear. Viral strategies to engage inhibitory NK cell receptors resulted in host adaptation and the generation of activating NK cell receptors, which further increases the complexity of CMV-host interaction. Together with our colleagues we have identified a novel upstream open reading frame (uORF), which plays a key role in the rescue of MHC-I surface expression by the viral m04 protein and is recognized by both activating and inhibitory Ly49 receptors. uORF encoded protein plays an important role in glycosylation, trafficking, affinity to Ly49 receptors as well as the peptide presentation of MHC-I. As a consequence, the virus can escape NK cell control in vivo. In the course of this project, we will elucidate the underlying molecular mechanism and dissect how this allows the virus to simultaneously evade both CTL killing and missing-self recognition by NK cells. Finally, we will clarify the molecular basis for the recognition of viral manipulation of MHC-I by activating NK cell receptors as well as its functional relevance in vivo. “