Major vault protein regulates cell growth/survival signaling through oxidative modifications.
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.
Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20057, USA.
Dividutta
D
Das
Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20057, USA.
Yi-Hsuan
YH
Wang
Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20057, USA.
Cheng-Ying
CY
Hsieh
Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20057, USA. Electronic address: ys82@georgetown.edu.
Yuichiro J
YJ
Suzuki
D001249:Asthma / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D020409:Molecular Motor Proteins / Q000235:genetics / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020394:Vault Ribonucleoprotein Particles / Q000378:metabolism*; D000097043:Interleukin-22; D000099187:Major Vault Protein
D005978:Glutathione; D007378:Interleukins; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains; D010982:Platelet-Derived Growth Factor; D020394:Vault Ribonucleoprotein Particles; D000097043:Interleukin-22; D000099187:Major Vault Protein; C103814:MYH9 protein, human
Airway; Glutathionylation; Major vault protein; Myosin-9; Redox signaling; Smooth muscle cells