Calpain 3 is a rapid-action, unidirectional proteolytic switch central to muscle remodeling

Abstract

Calpain 3 (CAPN3) is a cysteine protease that when mutated causes Limb Girdle Muscular Dystrophy 2A. It is thereby theonly described Calpain family member that genetically causes a disease. Due to its inherent instability little is known of itssubstrates or its mechanism of activity and pathogenicity. In this investigation we define a primary sequence motifunderlying CAPN3 substrate cleavage. This motif can transform non-related proteins into substrates, and identifies >300new putative CAPN3 targets. Bioinformatic analyses of these targets demonstrate a critical role in muscle cytoskeletalremodeling and identify novel CAPN3 functions. Among the new CAPN3 substrates are three E3 SUMO ligases of the ProteinInhibitor of Activated Stats (PIAS) family. CAPN3 can cleave PIAS proteins and negatively regulates PIAS3 sumoylase activity.Consequently, SUMO2 is deregulated in patient muscle tissue. Our study thus uncovers unexpected crosstalk betweenCAPN3 proteolysis and protein sumoylation, with strong implications for muscle remodeling. © 2010 de Morrée et al.