CAPN15 is a non-proteasomal, ubiquitin-directed calpain protease that regulates cell adhesion by cleaving E-cadherin

CAPN15, a member of the calpain protease family, contains a unique N-terminal region with five Zn²⁺-finger domains, including two ubiquitin-binding Npl4-type Zn²⁺-finger domains. However, the role of these domains in CAPN15 function remains unknown. In this study, we show that CAPN15 functions as a non-proteasomal, ubiquitin-directed protease, regulating cell surface E-cadherin. In cultured epithelial cells, CAPN15 KO resulted in densely packed morphology accompanied by the accumulation of cell surface E-cadherin, suggesting an increased cell adhesion. This defect was rescued by expressing WT CAPN15, but not protease-inactive or ubiquitin-binding-deficient CAPN15. CAPN15 recognizes the ubiquitinated E-cadherin-catenin complex through its N-terminal Zn²⁺-finger region and cleaves E-cadherin near its transmembrane domain. Since the truncated form is directed for lysosomal degradation, CAPN15 stands as a negative regulator of E-cadherin. E-cadherin accumulation was also observed in the epithelial tissues of Capn15 KO mice, further corroborating the in vivo relevance of CAPN15 to a mechanism controlling E-cadherin function. These findings reveal a previously unappreciated ubiquitin-dependent proteolytic pathway involving CAPN15 and provide important insight into the regulation of cell adhesion.