cAMP-induced phosphorylation of 26S proteasomes on Rpn6/PSMD11 enhances their activity and the degradation of misfolded proteins

This report describes an important new mechanism regulating protein degradation in mammalian cells through phosphorylation of the 26S proteasome. Treatments that raise cAMP and activate PKA cause phosphorylation of Rpn6/PSMD11, a subunit of the 19S regulatory complex. This modification enhances the proteasome's capacity to hydrolyze ubiquitinated proteins, ATP, and small peptides, and in cells stimulates the degradation of aggregation-prone proteins, including ones that cause neurodegenerative diseases (tau, SOD1, TDP43, and FUS). Our related collaborative study demonstrated that raising cAMP in brain promotes the clearance of aggregated tau in a mouse tauopathy model. This enhancement of proteasome activity and breakdown of misfolded proteins represents a new function of the cAMP/PKA pathway that offers a promising approach to treat proteotoxic diseases.