Inactivation of sestrin 2 induces TGF-beta signaling and partially rescues pulmonary emphysema in a mouse model of COPD.
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Cigarette smoking has been identified as one of the major risk factors and several predisposing genetic factors have been implicated in the pathogenesis of COPD, including a single nucleotide polymorphism (SNP) in the latent transforming growth factor (TGF)-beta binding protein 4 (Ltbp4)-encoding gene. Consistent with this finding, mice with a null mutation of the short splice variant of Ltbp4 (Ltbp4S) develop pulmonary emphysema that is reminiscent of COPD. Here, we report that the mutational inactivation of the antioxidant protein sestrin 2 (sesn2) partially rescues the emphysema phenotype of Ltbp4S mice and is associated with activation of the TGF-beta and mammalian target of rapamycin (mTOR) signal transduction pathways. The results suggest that sesn2 could be clinically relevant to patients with COPD who might benefit from antagonists of sestrin function.
Wempe
Frank
F
Department of Molecular Hematology, University of Frankfurt Medical School, 60590 Frankfurt am Main, Germany.
De-Zolt
Silke
S
Koli
Katri
K
Bangsow
Thorsten
T
Parajuli
Nirmal
N
Dumitrascu
Rio
R
Sterner-Kock
Anja
A
Weissmann
Norbert
N
Keski-Oja
Jorma
J
von Melchner
Harald
H
D000483:Alleles; D000818:Animals; D004195:Disease Models, Animal; D004790:Enzyme Induction; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D020868:Gene Silencing; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins / Q000172:deficiency; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins; D010544:Peroxidases; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D011506:Proteins / Q000235:genetics*; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011656:Pulmonary Emphysema / Q000150:complications / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000084622:Sestrins
D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D009687:Nuclear Proteins; D010544:Peroxidases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; D016212:Transforming Growth Factor beta; C529380:Sesn2 protein, mouse; D000084622:Sestrins; C546843:mTOR protein, mouse