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Regulation of Lung Fibrosis: the impact of Smad3 post-translational modification Jae Hyang Lim, DVM, PhD Associate Professor Department of Microbiology Ewha Womans University School of Medicine Streptococcus pneumoniae (Sp) is the most common cause of community-acquired pneumonia worldwide. Pneumococcal infections generally respond well to the treatment with susceptible antibiotics. Although clinical symptoms respond well to the antibiotics treatment, it takes longer to recover from radiologic pathology, and in some patients fibrotic scar tissues persist several weeks to several months. While most patients recover without significant complications, some develop permanent nonfunctional scar tissues (fibrosis). The molecular mechanism underlying this discrepancy remains to be elucidated. Transforming growth factor- (TGF)/Smad signaling pathway plays a critical role in the pathophysiology of pulmonary fibrosis. TGF binding to its membrane receptors activates Smad3, which in turn forms heterodimer complex with Smad4 and translocates to the nucleus where it regulates pro-fibrotic gene expression. To avoid aberrant fibrotic tissue remodeling, Smad3 protein activity must be tightly regulated. In the present study, we found that deubiquitinase CYLD regulates outcomes from S. pneumoniae infections by regulating Smad3 protein stability. Following tissue injury, S. pneumoniae activates Akt, which in turn phosphorylates glycogen synthase kinase 3 (GSK3) and inhibits GSK3-mediated proteasome dependent degradation of Smad3. CYLD promotes Smad3 degradation by deubiquitinating lysine 63 (K63)-specific polybuiqutination of Akt and, which in turn inhibits Akt-mediated inhibition of GSK3-mediated Smad3 degradation. Thus CYLD is an anti-fibrotic factor during tissues repair processes following tissue injury in lungs. We also found that ERK5, an atypical MAPK which is activated by TGF, positively regulates TGF signaling and subsequent profibrotic responses by promoting Smad3 acetylation. Taken together, these findings add novel molecular mechanisms for the tight regulation of TGF/Smad signaling and subsequent pro-fibrotic responses.
