Calpain- and ubiquitin-dependent proteolytic pathways modulate the cellular function and stability of the transcription factor YY1

Rapid degradation of transcriptional regulators underlies a wide range of cellular and developmental processes. The transcriptional repressor of myogenesis YY1 is preferentially proteolyzed during normal muscle cell differentiation and serum deprivation-induced apoptosis. The calcium-activated neutral protease calpain and ubiquitin-dependent proteases are both found to be associated with the degradation of YY1. Consistent with the promyogenic regulatory role of calpain, YY1 but not the myogenic factor SRF is readily cleaved by the endogenous as well as exogenous calpain II. YAF2, a novel zinc finger protein specifically interacting with YY1, is upregulated during skeletal and cardiac myogenesis, and greatly potentiates proteolytic cleavage of YY1 by calpain II. On the other hand, the late phase of myoblast apoptosis is accompanied by induction of protein ubiquitination, and both YY1 and SRF are found to be targeted for degradation by the ubiquitin proteosome pathway. In vitro ubiquitination assays further show that YY1 and SRF are ubiquitinated in reticulocyte lysates. The use of a series of YY1 deletion mutants show that proteolysis of YY1 by caipain II and ubiquitin proteases require the N- and C-terminal domains of YYI, respectively. These studies provide a mechanism through which caipain may promote myogenesis by selectively eliminating YY1 in a calcium-dependent fashion, and suggest that calpain and ubiquitin proteases may be differentially involved in the degradation of YY1.