October 3rd 2024

Published in MCP: Assessment of Kinome-Wide Activity Remodeling upon Picornavirus Infection

Published in MCP: Assessment of Kinome-Wide Activity Remodeling upon Picornavirus Infection

The CARE partner Utrecht University (UU) conducted an overview of the (de)regulation of kinase activities (kinome) by two picornaviruses during infection using a targeted mass spectrometry-based system-wide kinase activation assay (covering ~40% of the human kinome). The family Picornaviridae, a large family of small, non-enveloped viruses with a single stranded positive sense RNA genome, includes many well-known human and animal pathogens and are known to deregulate key host-cellular processes.

UU observed a considerable overlap in the kinome activity remodeling of the host cells infected by either coxsackievirus B3 (CVB3), an enterovirus, and encephalomyocarditis (EMCV), a cardiovirus. Both activate the MAPK pathways and the DNA damage response (DDR), although the dynamics of activation of specific kinases within these pathways were different for CVB3 or EMCV.

Moreover, during both CVB3 and EMCV infection, several kinases involved in regulating the cell cycle were inhibited – most of them having a role in mitosis – suggesting that both viruses regulate cell cycle, especially mitosis.

As the observed activation of several kinases upon CVB3 or EMCV infection suggests a role of these kinases in viral reproduction, UU administered 16 kinase inhibitors including MAPK pathway inhibitors, DDR inhibitors, an inhibitor of CDK9, and a pan-PAK kinase inhibitor. Nearly all 16 inhibitors could decrease viral reproduction, although most of them often only at relatively high concentrations. However, almost all inhibitors also reduced cell viability at these higher concentrations, illustrating a likely narrow therapeutic window balancing effective treatment and cellular toxicity.

Altogether, the data provide a quantitative understanding of the regulation of kinome activity induced by picornavirus infection, providing a resource important for developing novel antiviral therapeutic interventions. This work was important to establish assays and methodology to evaluate the impact of coronaviruses on host cells in CARE.

To learn more, click here:  Assessment of Kinome-Wide Activity Remodeling upon Picornavirus infection