RPGRIP1L and PKC beta II in desmoglein internalization

Project Summary The desmosomes are important cell-cell junctions. Genetic and autoimmune perturbation of the formation or function of desmosomes can lead to devastating or lethal even conditions, such as pemphigus, hypotrichosis, or arrhythmogenic right ventricular dysplasia. Thus, understanding the regulation of desmosomes under pathophysiological conditions will provide the foundation for the development of safe and effective therapies. In our preliminary study, we discovered that RPGRIP1L, a gene that is only known to be related to cilia or ciliopathy, is also involved in the formation of desmosomal junctions in the skin. The RPGRIP1L protein likely regulates desmosome formation through PKCßII, the aberrant activation of which, as we found, accelerates the internalization of desmogleins. The identification of PKCßII as an intermediate mediator of desmosome formation in this genetic model led to the discovery that PKCßII is also aberrantly upregulated in pemphigus. Preliminary data suggest that small molecule inhibition of PKCßII may be exploited as a novel therapeutic approach for pemphigus. The goal of this study is to understand the molecular mechanisms on how RPGRIP1L regulates PKCßII and how PKCßII regulates desmosome formation. We hypothesize that PKCßII mediates the internalization of membrane desmogleins through phosphorylating desmosomal proteins, whereas RPGRIP1L is required for efficient degradation of PKCßII through the ubiquitin-proteasome system. Perturbation of this regulatory mechanism will result in aberrant accumulation and activation of PKCßII, hence accelerated internalization of desmogleins. These hypotheses will be tested in Specific Aim 1 and 2, respectively, in both keratinocytes and passive transfer mouse models of pemphigus. Successful outcome of this study may not shift the paradigm on our current understanding of the functions of cilia-related genes, but may also demonstrate the feasibility of treating pemphigus through targeting PKCßII.