| First Author | Zimmerman KA | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 20 | Pages | 14584-98 |
| PubMed ID | 23564462 | Mgi Jnum | J:198580 |
| Mgi Id | MGI:5498422 | Doi | 10.1074/jbc.M112.447243 |
| Citation | Zimmerman KA, et al. (2013) Calreticulin regulates transforming growth factor-beta-stimulated extracellular matrix production. J Biol Chem 288(20):14584-98 |
| abstractText | Endoplasmic reticulum (ER) stress is an emerging factor in fibrotic disease, although precise mechanisms are not clear. Calreticulin (CRT) is an ER chaperone and regulator of Ca(2+) signaling up-regulated by ER stress and in fibrotic tissues. Previously, we showed that ER CRT regulates type I collagen transcript, trafficking, secretion, and processing into the extracellular matrix (ECM). To determine the role of CRT in ECM regulation under fibrotic conditions, we asked whether CRT modified cellular responses to the pro-fibrotic cytokine, TGF-beta. These studies show that CRT-/- mouse embryonic fibroblasts (MEFs) and rat and human idiopathic pulmonary fibrosis lung fibroblasts with siRNA CRT knockdown had impaired TGF-beta stimulation of type I collagen and fibronectin. In contrast, fibroblasts with increased CRT expression had enhanced responses to TGF-beta. The lack of CRT does not impact canonical TGF-beta signaling as TGF-beta was able to stimulate Smad reporter activity in CRT-/- MEFs. CRT regulation of TGF-beta-stimulated Ca(2+) signaling is important for induction of ECM. CRT-/- MEFs failed to increase intracellular Ca(2+) levels in response to TGF-beta. NFAT activity is required for ECM stimulation by TGF-beta. In CRT-/- MEFs, TGF-beta stimulation of NFAT nuclear translocation and reporter activity is impaired. Importantly, CRT is required for TGF-beta stimulation of ECM under conditions of ER stress, as tunicamycin-induced ER stress was insufficient to induce ECM production in TGF-beta stimulated CRT-/- MEFs. Together, these data identify CRT-regulated Ca(2+)-dependent pathways as a critical molecular link between ER stress and TGF-beta fibrotic signaling. |
