PIH1D1 and RPAP3, Components of the PAQosome: Emerging Roles in Cellular Physiology

The PAQosome (R2TP/PFDL complex) is a recently characterized co-chaperone of Hsp90 that orchestrates the assembly and stabilization of diverse macromolecular protein complexes essential for cellular homeostasis. It consists of RUVBL1, RUVBL2, PIH1D1, RPAP3 and a PFDL module consisting of prefoldin and prefoldin-like proteins. RPAP3 and PIH1D1 are subunits exclusively for the R2TP complex, and they act as central adaptors through their interactions with RUVBL1/2, Hsp90 and clients. Originally described in the context of ribonucleoprotein and PIKK assembly, evolving evidence now implicates PIH1D1 and RPAP3 in a broad spectrum of biological processes, including ciliogenesis, RNA silencing, DNA damage response, metabolic regulation, and oncogenesis. The mechanistic basis of substrate recognition, the phosphorylation-independent interactions, and the functional contribution of alternative PAQosome assemblies remain limited. This review highlights PIH1D1 and RPAP3 as dynamic proteins at the crossroads of protein homeostasis, signaling pathways, and diseases.