DPCD is a regulator of R2TP in ciliogenesis initiation through Akt signaling

R2TP is a chaperone complex consisting of the AAA+ ATPases RUVBL1 and RUVBL2, as well as RPAP3 and PIH1D1 proteins. R2TP is responsible for the assembly of macromolecular complexes mainly acting through different adaptors. Using proximity-labeling mass spectrometry, we identified deleted in primary ciliary dyskinesia (DPCD) as an adaptor of R2TP. Here, we demonstrate that R2TP-DPCD influences ciliogenesis initiation through a unique mechanism by interaction with Akt kinase to regulate its phosphorylation levels rather than its stability. We further show that DPCD is a heart-shaped monomeric protein with two domains. A highly conserved region in the cysteine- and histidine-rich domains-containing proteins and SGT1 (CS) domain of DPCD interacts with the RUVBL2 DII domain with high affinity to form a stable R2TP-DPCD complex both in cellulo and in vitro. Considering that DPCD is one among several CS-domain-containing proteins found to associate with RUVBL1/2, we propose that RUVBL1/2 are CS-domain-binding proteins that regulate complex assembly and downstream signaling. [Display omitted] •DPCD is an adaptor for the R2TP chaperone complex•R2TP-DPCD regulates ciliogenesis initiation of primary cilia•R2TP-DPCD interacts with p-AKT2 to control its phosphorylation levels•DPCD specifically interacts with the DII of RUVBL2 within the R2TP-DPCD complex The R2TP chaperone complex is responsible for assembly of macromolecular complexes. Here, Mao et al. identify DPCD as an adaptor of R2TP. R2TP-DPCD is found to regulate ciliogenesis initiation of primary cilia through interaction with AKT2 kinase to control its phosphorylation levels rather than its stability.