How does the desmosome-actin crosstalk regulate desmosome function?

Cells in stress-exposed tissues, e.g. heart muscle and coverings of body surfaces, are bound together by tiny structures called desmosomes, aberrant function of which causes diseases such as heart failure, defective wound healing, cancer spread and blistering diseases of the skin and oral cavity. Desmosomes are also important for normal development, where they stabilise developing tissues. It is therefore essential to understand how desmosome function is regulated.

We have shown that an important factor contributing to tissue toughness is that the ability of desmosomes to adopt a highly adhesive state known as hyper-adhesion. Hyper-adhesion is important for tissue strength, but also locks cells together restricting their movement. During wound healing, epidermal cells migrate to close the wound. The invasive spread of cancer cells also requires cell migration and in development cell movement generates the correct architecture of tissues.

When cells move and grow to establish cell sheets, they form new desmosomes that mature to become highly adhesive. When cell sheets are wounded they rapidly lose hyper-adhesion and downregulate desmosomes by internalising them. Little is known about how desmosomes assemble, change their adhesive state and how they are downregulated when this is needed.

Desmosomes have a characteristic structure made up of a few components and we have found that most of these components are stably integrated into the structure. However, one of them, called plakophilin (Pkp), moves rapidly from the periphery to central parts of the cell and vice versa. We think that this dynamic behaviour serves to transmit information (signals) within the cell and leads to changes in cell behaviour.

Normally desmosomes appear at the junctions between cells but studies have shown whole desmosome inside cells, as though one cell has "eaten" the desmosome! We have now induced cell separation in culture and shown that they do indeed engulf whole desmosomes. This is exciting because it enables us to investigate the mechanism behind a process that occurs in normal and diseased tissues.

Desmosome engulfment resembles a process called phagocytosis whereby cells of the immune system engulf extracellular particles, e.g. bacteria. Phagocytosis requires active contractile activity by the engulfing cell so as to surround the particle and draw it inside. Such contractility requires the action depends upon filamentous proteins called actin and myosin, similar to those involved in muscle contraction.

Functional actin and associated proteins are also important for desmosome regulation. Desmosomes are normally internally linked to other filaments called intermediate filaments (IF), rather than actin. Desmosomes link IF from cell-to-cell by, forming a scaffolding that gives strength to tissues.

However, IF possess nor contractile activity Hence the question that arises of how actins link up to desmosome to regulate their function when contractility is required?

We have pilot data showing that a number of proteins known to interact with actin are very close to desmosomes and we think that these are involved in regulation of desmosome adhesion and engulfment. Our data also suggest that the actin cytoskeleton influences signalling by Pkp. We will use state-of the-art microscopy to study how desmosomes become associated with the contractile machinery as they assemble and switch from hyper-adhesion to engulfment, and mass spectrometry to identify how actin binding proteins are involved in regulating desmosome function.

Finally, we will use molecular cell biology to determine the role Pkp in this process and in signalling cell behaviour.

Our results will both further our understanding of normal development and provide a basis for new therapies for major health problems such as chronic wounds, some types of heart failure, skin blistering diseases and, potentially, for limiting the spread of cancer.