Desmoplakin (green) uses keratins (red) and actin to reach desmosomes.

Cells rely on desmosomes to resist mechanical forces that can pull tissues apart. But how the components of these intercellular junctions arrive at the cell cortex and form the structure has been a matter of debate, with both membrane-bound and nonmembrane-bound precursors implicated. On page 1045, Godsel et al. report that nonmembrane-bound cytoplasmic desmoplakin motors outwards to form the structures.

The authors followed GFP-labeled desmoplakin, a key component of desmosomes, just before and after cells made contact with their neighbors. Prior to contact, GFP-desmoplakin was seen in cytoplasmic particles. Immediately after contact, the protein began to accumulate on the inner surface of the membrane at the site of contact.

Subsequently, more desmoplakin particles appeared in the cytoplasm, colocalizing with plakophilin-2 and often with intermediate filaments. These particles moved toward the site of contact, adding to the nascent structure. Inhibiting desmoplakin association with intermediate filaments or disrupting the actin cytoskeleton slowed desmosome formation.

A smaller subset of desmoplakin particles colocalized with membrane-bound Dsc2, a desmosomal cadherin. These particles were typically larger than those lacking Dsc2 and tended to be perinuclear. Because the team never saw such particles move toward sites of contact, they concluded that these were the remnants of old desmosomes, possibly headed for degradation.

The group must now determine what induces the desmoplakin–plakophilin-2 precursors to move to the membrane and how they are transported.