Abstract
Normal epithelial and endothelial renewal and healing after bacterial and viral challenges are essential for homeostasis along the intestine and the blood and lymphatic vessels. We thus investigated whether and how virus affects migration of human epithelial cells and specifically how the nucleocapsid protein (N) modulates the cellular proteome and interactome using human Caco-2 cells in a wound-healing assay with Hazara virus as a model. Here, Hazara virus blocked cell migration in a dose- and time-dependent manner, disrupted the actin cytoskeleton and specifically reduced the expression of the IQ-motif-containing GTPase-activating protein 1 (IQGAP1) and water channel aquaporin 6 (AQP6) that regulate cytoskeletal organization, water homeostasis and vesicle communication. Moreover, in the Caco-2 cell proteome, we identified several distinct groups of molecules associating with N upon Hazara virus infection, being involved in the ensemble of important cellular processes, e.g., chaperone activity, metabolism, cellular defense against infections, cell morphology, and migration. These events do not only facilitate the virus life cycle, but they are also crucial for membrane and cytoskeleton dynamics, cellular self-renewal and wound healing, being so essential for body integrity and homeostasis.
Highlights
Epithelial cells are positioned strategically to provide barriers to pathogens and other environmental agents
We showed recently that aquaporin 6 (AQP6), a water transporter and cytoskeleton interactor linked to an intracellular anion channel and involved in vesicle trafficking and sorting (Beitz et al, 2006; Nozaki et al, 2008), seems to have a protective role against Hazara virus infections (Molinas et al, 2016) (Figure 1, shown in yellow)
For the wounds created at 24 hpi, the rates of healing for cells infected with Hazara virus at multiplicities of infection (MOI) 2.0 were significantly suppressed at 30–52 h
Summary
Epithelial cells are positioned strategically to provide barriers to pathogens and other environmental agents. The epithelial cell barrier consists of a monolayer of cells that are constantly moving and renewed normally every 72 h in the gut This is controlled by a highly sophisticated interplay between the cytoskeleton, intercellular junctions, extracellular matrix, Virus-Affected Cell Migration and Proteome surface receptors, signal mediators and fluxes of solutes and water (Ivanov et al, 2010; Rodrigues and Granger, 2015; Friedl and Mayor, 2017). By such interplay with the cytoskeleton and signaling cascades, the AQP do assist directly and indirectly distinct processes, such as cell volume, signal transduction, metabolism, cell migration, and organelle physiology (Saadoun et al, 2005; Verkman, 2005; Loitto et al, 2009; Karlsson et al, 2013; Holm et al, 2016; Molinas et al, 2016)
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