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 PKC?II, the aberrant activation of which, as we found, accelerates the internalization of desmogleins. The identification of PKC?II as an intermediate mediator of desmosome formation in this genetic model led to the discovery that PKC?II is also aberrantly upregulated in pemphigus. Preliminary data suggest that small molecule inhibition of PKC?II 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 PKC?II and how PKC?II regulates desmosome formation. We hypothesize that PKC?II mediates the internalization of membrane desmogleins through phosphorylating desmosomal proteins, whereas RPGRIP1L is required for efficient degradation of PKC?II through the ubiquitin-proteasome system. Perturbation of this regulatory mechanism will result in aberrant accumulation and activation of PKC?II, 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 PKC?II.
Key components of the desmosomes are identified. Through studying of an unexpected blistering phenotype in a genetic mutant mouse model of Rpgrip1l, we discovered a previously unrecognized regulatory mechanism of the desmosome by which RPGRIP1L regulates PKC?II and desmoglein internalization. The proposed study is aimed at determining the molecular mechanism of the RPGRIP1L-PKC?II regulatory pathway. Understanding the functions of these regulators will help us to identify novel therapeutic strategies for related diseases, such as pemphigus.
