Work

ERK-mediated phosphorylation modulates the autolytic processing of the cysteine protease CAPN3

Year: 2026

Type: article

Abstract: -dependent cysteine protease predominantly expressed in skeletal muscles. Mutations in CAPN3 are associated with limb-girdle muscular dystrophy R1 (LGMDR1), an autosomal recessive muscular dystrophy. CAPN3 is uniquely activated by rapid autolytic processing; however, the mechanisms regulating this activation are poorly understood. Here we show that phosphorylation regulates CAPN3 autolytic processing in living cells. We found that ouabain, a cardiac glycoside, activated ERK, which induced the phosphorylation of CAPN3 at S19 located within its N-terminal region. This phosphorylation promoted the N-terminal cleavage without altering the autolytic insertion sequence 1 (IS1) processing of CAPN3 or its subcellular localization in skeletal muscle cells. Notably, treatment of cultured skeletal muscle cells with insulin-like growth factor I (IGF-1), which can activate the ERK pathway, also induced S19 phosphorylation, suggesting that this modification can occur downstream of physiologically relevant extracellular signaling. These results demonstrate that ERK-mediated phosphorylation provides a regulatory mechanism for modulating N-terminal processing of CAPN3 without substantially affecting IS1 autolytic processing.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2026.113638

Authors: Chihiro Hisatsune, Fumiko Shinkai-Ouchi, Mayumi Shindo, Shoji Hata, Yasuko Ono

Institutions: Tokyo Metropolitan Institute of Medical Science, Saitama Medical University

Language: English

Topic: Calpain Protease Function and Regulation

Subfield: Cell Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $3,430

Funder: Japan Society for the Promotion of Science