Disrupted desmosomes drive fibrosis

Dubash et al. describe how the loss of desmosomal proteins activates a profibrotic signaling pathway in cardiomyocytes.

Plakophilin-2 (PKP2) is a key structural component of desmosomes, intercellular adhesions that are particularly important for holding cells together in mechanically stressed tissues such as the heart. Accordingly, mutations in PKP2 disrupt the junctions between neighboring cardiomyocytes and cause arrhythmogenic cardiomyopathy. This disease is also associated with the formation of fibrotic lesions, but how the loss of PKP2 contributes to tissue fibrosis remains unknown.

Dubash et al. found that knocking down PKP2 in cultured cardiomyocytes, or removing one copy of the PKP2 gene from mice, increased expression of the profibrotic growth factor TGF-β1. This, in turn, activated a p38 MAP kinase–dependent signaling pathway that up-regulated multiple inflammatory and extracellular matrix proteins known to promote tissue fibrosis.

PKP2’s desmosomal binding partner, Desmoplakin, was destabilized in PKP2’s absence, Dubash et al. discovered, and restoring Desmoplakin levels reversed the up-regulation of TGF-β1 and its profibrotic effectors. Knocking down Desmoplakin, in contrast, was sufficient to activate TGF-β1 signaling even in the presence of PKP2.

First author Adi Dubash says that disrupted desmosomes may induce fibrosis in several other human diseases. The next question, he says, is to determine how the loss of Desmoplakin up-regulates TGF-β1 transcription.