Trps1 enhances Hdac4 and Gli3 protein stability and nuclear localization independent of PKA and PP2A signaling

The growth of endochondral bones relies on the coordinated proliferation and hypertrophy of chondrocytes. This process is governed by several transcription factors and epigenetic modifiers that regulate distinct steps, likely by assembling into larger complexes that bind to DNA. The transcription factor Trps1 has previously been shown to interact with the activator form of Gli3 (Gli3A) and the histone deacetylase Hdac4, two critical regulators of chondrocytes proliferation and differentiation. Here, we show that the interaction with Trps1 increases the abundance of both proteins and promotes their nuclear localization. We further demonstrate that Trps1 acts independently of PKA and PP2A activity, which have been reported to regulate the nuclear localization and activity of Gli3A and Hdac4. Trps1 and Gli3A complexes were predominantly found in proliferating chondrocytes, whereas Trps1 and Hdac4 interactions occurred more frequently in prehypertrophic chondrocytes, suggesting differentiation-specific changes in protein interactions. These findings reveal the regulation of protein abundance and nuclear availability as a novel mechanism by which Trps1 controls gene expression during chondrocyte differentiation.