Abstract
Major vault protein (MVP) is the major component of the vault particle whose functions are not well understood. One proposed function of the vault is to serve as a mechanism of drug transport, which confers drug resistance in cancer cells. We show that MVP can be found in cardiac and smooth muscle. In human airway smooth muscle cells, knocking down MVP was found to cause cell death, suggesting that MVP serves as a cell survival factor. Further, our laboratory found that MVP is S-glutathionylated in response to ligand/receptor-mediated cell signaling. The S-glutathionylation of MVP appears to regulate protein-protein interactions between MVP and a protein called myosin heavy chain 9 (MYH9). Through MYH9 and Vsp34, MVP may form a complex with Beclin-1 that regulates autophagic cell death. In pulmonary vascular smooth muscle, proteasome inhibition promotes the ubiquitination of MVP, which may function as a mechanism of proteasome inhibition-mediated cell death. Investigating the functions and the regulatory mechanisms of MVP and vault particles is an exciting new area of research in cardiovascular/pulmonary pathophysiology.
Highlights
Major vault protein (MVP) is the major component of the vault particle whose functions are not well understood
These results suggest that both MVP and vault poly(ADP-ribose) polymerase (vPARP) are needed for cell survival, strengthening the notion that these proteins act as part of the vault particle
Since myosin heavy chain 9 (MYH9) has been shown to interact with Vps34[18], which binds to Beclin-1 for the activation of autophagy[3], we propose that Beclin-1, Vps34 and MYH9 form a complex that mediates cell death and that the ROS-dependent S-glutathionylation of MVP triggers the binding of MYH9 to the vault complex, inhibiting Beclin-1-dependent cell death (Fig. 8)
Summary
Studies of MVP in smooth muscle cells (SMCs) had never been conducted until our publications, which show that human airway SMCs[2] and lung vascular SMCs[17] express MVP. Immunohistochemistry demonstrates the expression of MVP in the pulmonary vascular smooth muscle, which was remarkably found to be higher than that in any other parts of the lung in normal healthy rats (Fig. 2A). Immunohistochemistry shows the expression of MVP in cardiac muscle as well as in coronary artery smooth muscle in normal rats (Fig. 2B)
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