Cytomegaloviruses (CMVs) have co-evolved with their mammalian hosts for millions of years, leading to remarkable host specificity and high infection prevalence. Macrophages, which already populate... Show moreCytomegaloviruses (CMVs) have co-evolved with their mammalian hosts for millions of years, leading to remarkable host specificity and high infection prevalence. Macrophages, which already populate barrier tissues in the embryo, are the predominant immune cells at potential CMV entry sites. Here we show that, upon CMV infection, macrophages undergo a morphological, immunophenotypic, and metabolic transformation process with features of stemness, altered migration, enhanced invasiveness, and provision of the cell cycle machinery for viral proliferation. This complex process depends on Wnt signaling and the transcription factor ZEB1. In pulmonary infection, mouse CMV primarily targets and reprograms alveolar macrophages, which alters lung physiology and facilitates primary CMV and secondary bacterial infection by attenuating the inflammatory response. Thus, CMV profoundly perturbs macrophage identity beyond established limits of plasticity and rewires specific differentiation processes, allowing viral spread and impairing innate tissue immunity. Show less
Sostaric, N.; O'Reilly, F.J.; Giansanti, P.; Heck, A.J.R.; Gavin, A.C.; Noort, V. van 2018
Protein post-translational modifications (PTMs) have an indispensable role in living cells as they expand chemical diversity of the proteome, providing a fine regulatory layer that can govern... Show moreProtein post-translational modifications (PTMs) have an indispensable role in living cells as they expand chemical diversity of the proteome, providing a fine regulatory layer that can govern protein-protein interactions in changing environmental conditions. Here we investigated the effects of acetylation and phosphorylation on the stability of subunit interactions in purified Saccharomyces cerevisiae complexes, namely exosome, RNA polymerase II and proteasome. We propose a computational framework that consists of conformational sampling of the complexes by molecular dynamics simulations, followed by Gibbs energy calculation by MM/GBSA. After benchmarking against published tools such as FoldX and Mechismo, we could apply the framework for the first time on large protein assemblies with the aim of predicting the effects of PTMs located on interfaces of subunits on binding stability. We discovered that acetylation predominantly contributes to subunits' interactions in a locally stabilizing manner, while phosphorylation shows the opposite effect. Even though the local binding contributions of PTMs may be predictable to an extent, the long range effects and overall impact on subunits' binding were only captured because of our dynamical approach. Employing the developed, widely applicable workflow on other large systems will shed more light on the roles of PTMs in protein complex formation. Show less
