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Cell Signal. 2016 Jan;28(1):12-8. doi: 10.1016/j.cellsig.2015.10.007. Epub 2015 Oct 22.

Major vault protein regulates cell growth/survival signaling through oxidative modifications.

Author information

1
Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20057, USA.
2
Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20057, USA. Electronic address: ys82@georgetown.edu.

Abstract

Major vault protein forms a hollow, barrel-like structure in the cell called the vault, whose functions and regulation are not well understood. The present study reports that major vault protein regulates growth/survival signaling in human airway smooth muscle cells through oxidative modifications. The promotion of protein S-glutathionylation by asthma mediators such as interleukin-22 and platelet-derived growth factor or by knocking down glutaredoxin-1 or thioredoxin activated cell growth signaling. Mass spectrometry identified that major vault protein is glutathionylated. Major vault protein knockdown enhanced cell death and inhibited STAT3 and Akt signaling. We identified a protein partner of major vault protein that is regulated by glutaredoxin-1, namely myosin-9, which was found to serve as a cell death factor. Knocking down myosin-9 or promoting protein S-glutathionylation by knocking down glutaredoxin-1 inhibited the death of airway smooth muscle cells by heating to simulate bronchial thermoplasty, a clinically successful procedure for the treatment of severe asthma. These results establish a novel signaling pathway in which ligand/receptor-mediated oxidation promotes the S-glutathionylation of major vault protein, which in turn binds to myosin-9 to suppress the heating-induced death of airway smooth muscle cells.

KEYWORDS:

Airway; Glutathionylation; Major vault protein; Myosin-9; Redox signaling; Smooth muscle cells

PMID:
26499037
PMCID:
PMC4679458
DOI:
10.1016/j.cellsig.2015.10.007
[Indexed for MEDLINE]
Free PMC Article

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