Inactivation of sestrin 2 induces TGF-β signaling and partially rescues pulmonary emphysema in a mouse model of COPD

Abstract

SUMMARY 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)-β 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-β 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.

Expression of a novel stress-inducible protein, sestrin 2, in rat glomerular parietal epithelial cells

“…In addition, sestrin 2 inhibits mammalian target of rapamycin (mTOR) signaling through a redox-independent mechanism, by activating AMP-activated protein kinase (AMPK) and phosphorylating tuberous sclerosis protein 2 (TSC2) (5). Although sestrin 2 knockout mice are reported to be fully viable and do not display any gross developmental abnormalities (30), a recent study (19) has shown that deletion of sestrin 2 exacerbates obesity-induced mTOR activation, glucose intolerance, insulin resistance, and hepatosteatosis.…”

Sestrins Link Tumor Suppressors with the AMPK-TOR Signaling Network

“…Sesn2 overexpression in 293 cells stimulates cell death [119]. Sestrins also modulate cell viability under stress condition, protecting from oxidative stress, but supporting cell death in response to genotoxic stress [119,123,143,147]. Cell death in response to -irradiation is regulated in an AMPK-dependent manner and Sesn2 plays a major role in regulation of AMPK phosphorylation in response to genotoxic stress [40,41,143].…”

“…It was shown that R-Smads, Smad1-5, are substrates of TGF receptors, activated by TGF, while others are activated by other members of the TGF family via interaction with relevant receptors. Phosphorylated Smad2 and Smad3 form heteromeric complexes with Smad4, which translocate to the nucleus where they bind Smad-dependent promoters and activate expression of a number of genes such as -smooth muscle actin (SMA), connective tissue growth factor (CTGF) and matrix metalloproteinase 2 (MMP2) involved in regulation of cell growth, differentiation and migration [147,152]. TGF also controls other signaling pathways through RhoA, Cdc42, Rac1, Ras, PI3K, PP2A, MEKK1, TAK1 and DAXX proteins.…”

“…Dysregulation in TGFb-dependent signaling contributes to fibrosis, cancer, cardiovascular and congenital diseases [150]. Sesn2-deficiency leads to activation of TGF signaling pathways in lung as well as in mouse lung fibroblasts (MLF) as indicated by increased phosphorylation of Smad2 and Smad3, and elevated expression of TGFb targets such as -SMA, connective tissue growth factor (CTGF) and MMP2 [147]. It has been also shown that inactivation of Sesn2 in MLF activates mTORC1, and TGF played a role in this process potentially stimulating the PI3K-AKT pathway [147] (Fig.5).…”

“…Interestingly, according to another work, Sesn2 activity can complicate some aspects of COPD via negative regulation of TGFβ signaling which mitigates emphysema phenotype in mice. Thus, inactivation of Sestrins has some therapeutic potential under some COPD conditions, although more work has to be done to elucidate the exact role of Sestrins in COPD and other respiratory diseases [147].…”