JADE family proteins regulate proteasome abundance and activity

Abstract

The JADE protein family (JADE1/2/3) has been implicated in a broad range of cellular functions, including WNT signaling, cell cycle control, regulated cell death, and transcriptional regulation through histone acetyltransferase complexes. All three paralogs share high sequence similarity and contain two PHD zinc finger domains. JADE1 has additionally been associated with cilia-related proteins and genetic disorders affecting kidney architecture and function. Despite their widespread expression, the molecular roles of JADE proteins remain incompletely understood. Here, we identify JADE proteins as regulators of proteasome abundance and activity. Using kidney cells as a model, we demonstrate that loss of any single JADE protein led to a marked upregulation of almost all components of the 26S proteasome. Regulation occurred at the post-translational level and was not the consequence of increased transcription. Consistent with a role for JADE proteins in regulating overall proteasomal abundance, JADE-deficient cells displayed elevated proteasomal activity, while ectopic expression of JADE1, JADE2, or JADE3 reduced proteasomal function. Co-immunoprecipitation experiments confirmed the interaction between JADE1 and multiple proteasomal subunits, supporting a direct role of JADE proteins in modulating proteasome turnover, stability and abundance. These findings reveal a novel function of JADE proteins in proteostasis and suggest that their previously reported cellular roles may, in part, be mediated through regulation of the ubiquitin-proteasome system.