Microcephaly-associated protein WDR62 supports purine metabolism by interacting with co-chaperone BAG2

TL;DR

The protein WDR62, linked to microcephaly, helps regulate purine metabolism by interacting with BAG2, affecting cell survival and brain development.

Contribution

WDR62 is shown to regulate purine metabolism through interaction with BAG2, a novel function beyond its known roles in cell division and brain development.

Findings

WDR62 interacts with BAG2 to regulate purine metabolism enzymes under stress.

WDR62 loss destabilizes HPRT and causes nucleoside accumulation.

WDR62 or HPRT depletion in mouse cortex alters neural precursor cell behavior.

Abstract

Inherited mutations in the spindle pole-associated scaffold protein WDR62 cause autosomal recessive primary microcephaly. Previous research has characterised the roles of WDR62 in the regulation of spindle dynamics, cell division, and brain development. Here, we identify a new function of this protein in regulating purine metabolism. WDR62 interacts directly with BAG2, a co-chaperone of HSP70/90. Under stress conditions, WDR62 and BAG2 re-localise to cytoplasmic granules enriched for enzymes involved in purine synthesis (PFAS) and salvage (HPRT). In WDR62-deficient cells, purine synthesis is impaired, while purine deprivation leads to cytotoxicity and nucleoside accumulation. Furthermore, in these cells elevated BAG2 levels are linked to HPRT destabilisation, which can be reversed by BAG2 knockdown. Notably, microcephaly-associated WDR62 mutations disrupt interaction with BAG2 and fail to restore HPRT levels. In utero depletion of WDR62 or HPRT in the mouse neocortex causes premature delamination and migration of neural precursor cells. Interestingly, HPRT loss enhances self-renewal and proliferation of these precursors, contrasting with the reduced proliferation and precocious differentiation observed upon WDR62 loss. Our study identifies regulatory functions of WDR62 in purine metabolism that may contribute to primary microcephaly.

The scaffold protein WDR62 has known centrosomal roles and is linked to microcephaly. This study shows WDR62 to also support purine metabolism by stabilizing key metabolic enzymes through its interaction with the co-chaperone BAG2.

Wild-type WDR62, but not its inherited microcephaly-associated mutations, interacts directly with co-chaperone BAG2.Cellular stress induces re-localization of WDR62 and BAG2 to cytoplasmic granules, where purine metabolic enzymes are concentrated.WDR62 loss destabilizes the purine salvage enzyme HPRT by increasing BAG2 levels.WDR62 loss results in nucleoside accumulation and sensitization of cells to purine depletion.In the developing mouse cortex, depletion of WDR62 or HPRT alters the proliferation and differentiation of neural precursor cells.

Wild-type WDR62, but not its inherited microcephaly-associated mutations, interacts directly with co-chaperone BAG2.

Cellular stress induces re-localization of WDR62 and BAG2 to cytoplasmic granules, where purine metabolic enzymes are concentrated.

WDR62 loss destabilizes the purine salvage enzyme HPRT by increasing BAG2 levels.

WDR62 loss results in nucleoside accumulation and sensitization of cells to purine depletion.

In the developing mouse cortex, depletion of WDR62 or HPRT alters the proliferation and differentiation of neural precursor cells.

Loss of WDR62 or of the purine salvage enzyme HPRT in the mouse neocortex impacts neural precursor cell differentiation.

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