Cells control the junction protein desmoplakin by methylating and phosphorylating its tail, Albrecht et al. show.

Desmosomes are heavy-duty junctions that link cells in tissues that undergo severe strain, such as in the heart and skin. Desmoplakin is a key component of the desmosome, since it anchors the intermediate filaments of the cytoskeleton to sites of cell–cell contact. Albrecht et al. determined how phosphorylation and methylation of desmoplakin’s tail affect the protein’s interaction with the cytoskeleton.

The kinase GSK3 phosphorylated six serines on desmoplakin’s tail, and its loss spurred the protein to shift from desmosomes to the intermediate filaments. Blocking GSK3 slowed desmoplakin’s relocation from the intermediate filaments to the cells’ boundaries during desmosome assembly.

Methylation of four arginine residues in desmoplakin’s tail had similar effects as phosphorylation. The team also found that methylation of one particular arginine, R2834, which is mutated in patients with arrhythmogenic cardiomyopathy, was necessary for phosphorylation of most tail serine residues because this alteration drew GSK3 to desmoplakin. Mutating this arginine weakened intercellular connections, causing cell layers to break apart when under mechanical stress.

The results show that phosphorylation and methylation make desmoplakin more dynamic. Cells might be able to fine-tune desmoplakin’s characteristics by adding and removing phosphates and methyl groups. Thus, they could direct the protein to cell boundaries when desmosomes are forming and curtail its movement when the junctions are complete.

, et al
J. Cell Biol.

Author notes

Text by Mitch Leslie