Heat shock protein DNAJA2 controls insulin signaling and glucose homeostasis by preventing spontaneous insulin receptor endocytosis.

Dysregulation of heat shock protein DNAJA2 induces genomic instability and was consequently hypothesized to promote tumorigenesis. However, DNAJA2 knockout mice do not develop cancer but exhibit neonatal lethality and the underlying mechanism remains unknown. Here, we demonstrate that DNAJA2 maintains homeostatic glucose metabolism by regulating insulin signaling. Mechanistically, DNAJA2 binds to the insulin receptor (IR) and prevents adaptor protein 2 (AP2)-mediated spontaneous IR endocytosis by inhibiting the IR-AP2 interaction. Thus, DNAJA2 defects lead to reduced IR localization on the plasma membrane and suppression of the insulin-stimulated signaling cascade, thereby inhibiting glycogen synthesis and storage in the liver during embryogenesis, further resulting in neonatal lethality of DNAJA2-deficient mice. Analysis of public datasets reveals a strong association between DNAJA2 and metabolic phenotypes, including type 2 diabetes mellitus (T2DM) and obesity, in both humans and mice. In conclusion, our study elucidates the mechanism by which DNAJA2 regulates IR endocytosis, insulin signaling and glucose metabolism, shedding light on the pathogenesis of metabolic disorders.