Calcium signals and calpain-dependent necrosis are essential for release of Coxsackievirus B from polarized intestinal epithelial cells

Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Molecular biology of the cell (Impact Factor: 4.47). 07/2011; 22(17):3010-21. DOI: 10.1091/mbc.E11-02-0094
Source: PubMed


Coxsackievirus B (CVB), a member of the enterovirus family, targets the polarized epithelial cells lining the intestinal tract early in infection. Although the polarized epithelium functions as a protective barrier, this barrier is likely exploited by CVB to promote viral entry and subsequent egress. Here we show that, in contrast to nonpolarized cells, CVB-infected polarized intestinal Caco-2 cells undergo nonapoptotic necrotic cell death triggered by inositol 1,4,5-trisphosphate receptor-dependent calcium release. We further show that CVB-induced cellular necrosis depends on the Ca(2+)-activated protease calpain-2 and that this protease is involved in CVB-induced disruption of the junctional complex and rearrangements of the actin cytoskeleton. Our study illustrates the cell signaling pathways hijacked by CVB, and perhaps other viral pathogens, to promote their replication and spread in polarized cell types.

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    • "Some examples include the involvement of oxidative stress in rhinovirus-mediated dissociation of ZO-1 from TJ complex [61]. Coxsackievirus B infection was shown to induce necrotic cell death as a result of cleavage of some of the junctional proteins by calpain, a calcium-dependent protease [62]. Our inhibitor data suggests that in JEV-infected epithelial cells, inhibition of apoptosis, proteasomal degradation or oxidative stress pathways failed to prevent claudin-1 degradation but bafilomycin A1, which prevents acidification of endosomes/lysosomes, was successful in blocking claudin-1 degradation indicating a role for lysosomal targeting of claudin-1 in barrier disruption. "
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    • "We found that expression of the CVB 3C pro cysteine protease was sufficient to induce many of the alterations in the actin cytoskeleton observed during CVB infection, including a loss of stress fibers and breakdown of FAs as well as induction of the relocalization of FAK from FAs (Figure S4E). As neither CVB infection nor 3C pro expression leads to cleavage of vinculin or other FA-associated components (Bozym et al., 2011, and data not shown), these findings suggest that loss of FAK association with FAs induces widespread effects on many FA-associated components. We also found that expression of 3C pro induced a significant loss of endogenous FAK expression and the appearance of a $100 kDa N-terminal cleavage fragment (Figure 5B). "
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