The microcephaly protein WDR62 regulates cellular purine metabolism through the HSP70/HSP90 chaperone machinery.
Inherited mutations in WD repeat-containing protein 62 (WDR62) are associated with microcephaly (MCPH2). While WDR62 plays important roles in mitosis and centriole biogenesis, additional WDR62 functions may cause abnormal brain growth. Here, we reveal a novel WDR62 role in the molecular chaperone network regulating purine metabolism. In response to hyperosmotic stress, WDR62 redistributes to purinosomes--phase-separated membraneless assemblies of purine metabolic enzymes and their chaperones. While WDR62 is not needed for purinosome formation, its loss disrupts purine homeostasis, resulting in the accumulation of purine nucleotide intermediates and a reduction in the levels of hypoxanthine-guanine phosphoribosyl transferase (HPRT), a key purine salvage enzyme. We link this to WDR62s interaction with Bcl2-associated athanogene 2 (BAG2), a co-chaperone that modulates the function of HSP70/90. In cells lacking WDR62, BAG2 levels are elevated and HPRT stability is reduced. Knocking down BAG2 in these cells restores HPRT levels, underscoring the crucial role of WDR62-BAG2 interactions in chaperone-mediated stability and turnover of metabolic pathway enzymes. Notably, common microcephaly-associated mutations in WDR62 alter its interaction with BAG2, suggesting that purine metabolic defects resulting from WDR62 mutations may underlie microcephaly in humans.