Actin maturation requires the ACTMAP/C19orf54 protease

Protein synthesis generally starts with a methionine which is removed during translation but actin molecules defy this rule. Instead, the synthesis of cytoplasmic actin involves non-canonical excision of the acetylated-methionine by an unidentified enzyme after translation. Here, we identified C19orf54/ACTMAP (ACTin MAturation Protease) as a factor needed for the production of mature actin. Ablation of ACTMAP resulted in viable mice supported by a cytoskeleton composed of immature actin molecules across all tissues. ACTMAP loss led to decreased muscle function characterized by shortening of the actin filaments in the sarcomeric structure and progressive accumulation of centralized nuclei in muscle fibers, a common hallmark of myopathies. Thus, ACTMAP encodes the missing factor required for the synthesis of mature actin and regulates specific actin-dependent traits in vivo.