Programmed cell death protein 5 may exert its apoptotic function through CCT

Abstract

Phosducin‐like protein 1 (PhLP1) was recently shown to be a co‐chaperone with the cytosolic chaperonin complex (CCT) in the folding and assembly of nascent G protein βγ dimers and Gβ5‐RGS proteins. However, other possible functions of PhLP1 warrant investigation. A co‐immunoprecipitation proteomics screen indicated PhLP1 interacts with a known tumor suppressor, programmed cell death 5 protein (PDCD5), which is implicated in apoptosis. Subsequent experiments showed PDCD5 associates with PhLP1 indirectly via a ternary complex with CCT and had no effect on PhLP1‐mediated Gβγ assembly. Previous studies suggested that PDCD5 translocates rapidly from the cytoplasm to the nucleus during the initial stages of apoptosis. However, our results indicate that PDCD5 is exclusively cytosolic in both resting and apoptotic cells, thus its apoptotic function is also cytosolic. Co‐immunoprecipitation proteomics screens show that PDCD5 interacts strongly with CCT and β‐tubulin. Cryo‐EM studies show a complex of PDCD5 and CCT, interacting at one of the apical domains. Moreover, biochemical analyses suggest that PDCD5 phosphorylation increases its binding to CCT during apoptosis and when bound to CCT, PDCD5 blocks β‐tubulin folding. We propose that PDCD5 binds to the apical domain of CCT as a co‐chaperone or inhibitor of CCT substrates involved in cell cycle progression or apoptosis. This research was funded by an NIH grant.