Abstract
Autosomal recessive mutations in the cytolinker protein plectin account for the multisystem disorders epidermolysis bullosa
simplex (EBS) associated with muscular dystrophy (EBS-MD), pyloric atresia (EBS-PA), and congenital myasthenia (EBS-CMS).
In contrast, a dominant missense mutation leads to the disease EBS-Ogna, manifesting exclusively as skin fragility. We have
exploited this trait to study the molecular basis of hemidesmosome failure in EBS-Ogna and to reveal the contribution of
plectin to hemidesmosome homeostasis. We generated EBS-Ogna knock-in mice mimicking the human phenotype and
show that blistering reflects insufficient protein levels of the hemidesmosome-associated plectin isoform 1a. We found that
plectin 1a, in contrast to plectin 1c, the major isoform expressed in epidermal keratinocytes, is proteolytically degraded,
supporting the notion that degradation of hemidesmosome-anchored plectin is spatially controlled. Using recombinant
proteins, we show that the mutation renders plectin’s 190-nm-long coiled-coil rod domain more vulnerable to cleavage by
calpains and other proteases activated in the epidermis but not in skeletal muscle. Accordingly, treatment of cultured EBSOgna
keratinocytes as well as of EBS-Ogna mouse skin with calpain inhibitors resulted in increased plectin 1a protein
expression levels. Moreover, we report that plectin’s rod domain forms dimeric structures that can further associate laterally
into remarkably stable (paracrystalline) polymers. We propose focal self-association of plectin molecules as a novel
mechanism contributing to hemidesmosome homeostasis and stabilization.