Fig. 7: A working model describing the mechanism by which DNAJA2 regulates insulin signaling and glucose metabolism. | Nature Communications

Fig. 7: A working model describing the mechanism by which DNAJA2 regulates insulin signaling and glucose metabolism.

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

Fig. 7

A In DNAJA2-proficient hepatocytes, DNAJA2 directly binds to the intracellualr TKD domian of IRβ, which blocks the IRβ-AP2 interaction and inhibits AP2-mediated IR endocytosis. Consequently, the majority of IR are localized on the plasma membrane (PM), and can be readily activated by the coming insulin efficiently. The normal insulin signaling then drives homeostatic glucose metabolism, glycogen synthesis and tissue growth. B In DNAJA2-deficient cells, the AP2 complex binds to the membrane IR and promotes IR interlization through clathrin-mediated endocytosis, thereby significantly reducing the IR localization on the PM. As a result, the insulin is unable to activate the insulin signaling cascade, which leads to insulin resistance, and disrupts glucose metabolism including glycogen synthesis, and tissue growth.

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