A mutation in PKP2, the gene encoding plakophilin 2, results in reduced abundance of desmosomal proteins via a mechanism that involves the ubiquitin–proteasome system (UPS). This finding, from a study in Sci. Transl. Med., shows that desmosomal protein degradation might underlie the development of arrhythmogenic cardiomyopathy (ACM) caused by a variant in PKP2.