Proteasomal regulation of pulmonary fibrosis

Abstract

It is estimated that, combined, 400,000 people are diagnosed with idiopathic pulmonary fibrosis (IPF) or acute lung injury/acute respiratory distress syndrome annually in the United States, and both diseases are associated with an unacceptably high mortality rate. Although these disorders are distinct clinical entities, they share pathogenic mechanisms that may provide overlapping therapeutic targets. One example is fibroblast activation, which occurs concomitant with acute lung injury as well as in the progressive fibrosis of IPF. Both clinical entities are characterized by elevations of the profibrotic cytokine, transforming growth factor (TGF)-beta1. Protein degradation by the ubiquitin-proteasomal system modulates TGF-beta1 expression and signaling. In this review, we highlight the effects of proteasomal inhibition in various animal models of tissue fibrosis and mechanisms by which it may regulate TGF-beta1 expression and signaling. At present, there are no effective therapies for fibroproliferative acute respiratory distress syndrome or IPF, and proteasomal inhibition may provide a novel, attractive target in these devastating diseases.

Figure 1.

Transforming growth factor (TGF)-β1 binding of the activin receptor-like kinase (ALK5) receptor induces the phosphorylation of Smad2,3 (R-smads). Smad2,3 forms a complex with Smad4, which then translocates to the nucleus, where it interacts with transcriptional coactivators, such as p300, to regulate gene transcription. Repressors and corepressors, such as peroxisome proliferator–activated receptor (PPAR)-γ, cellular homolog of Sloan-Kettering virus (Ski), and Ski novel gene N (SnoN), are other proteins that regulate the system.

Figure 2.

Conjugation of ubiquitin to the protein substrate. Ubiquitin (Ub) is activated by E1, an ATP-dependent activating enzyme. Ubiquitin is then transferred to E2, a conjugating enzyme, which further transfers activated ubiquitin to a unique ubiquitin ligase E3. Polyubiquitin is generated by the addition of multiple ubiquitin moieties.