Loss of CHIP Expression Perturbs Glucose Homeostasis and Leads to Type II Diabetes Through Defects in Microtubule Polymerization and Glucose Transporter Localization

Abstract

Glucose homeostasis requires insulin signaling throughout the body to maintain physiological blood glucose levels. The loss of insulin sensitivity, or insulin resistance, is associated with a myriad of diseases including Type II diabetes, atherosclerosis, abdominal obesity, and hypertension. Cellular protein quality control pathways involving the chaperone and ubiquitin proteasome system have been associated with the pathophysiology of insulin resistance, but the molecular details are incompletely understood. We and others have previously demonstrated a role for the co‐chaperone and E3‐ubiquitin ligase CHIP (Carboxyl terminus of HSC70‐Interacting Protein) in the regulation of several metabolism‐associated proteins including AMPK, SirT6, AKT, SGK‐1 and PTEN. We demonstrate that mice genetically deficient in CHIP (gene locus Stub1) exhibit a striking Type II diabetes‐like phenotype, including impaired glucose tolerance, decreased insulin sensitivity, and decreased insulin‐stimulated glucose uptake in skeletal muscle in comparison to wild‐type animals. Interestingly, CHIP‐depleted C2C12 skeletal myoblasts exhibited a profound defect in the translocation of the glucose transporter Glut4 to the plasma membrane after glucose/insulin stimulation. The impairment of Glut4 translocation was accompanied by a decrease in both tubulin polymerization and phosphorylation of stathmin (Ser16), a microtubule‐regulating protein required for polymerization‐dependent protein trafficking. PIP3, required for microtubule reorganization, was sustained in wild‐type C2C12 cells following stimulation whereas CHIP‐depleted C2C12s exhibited only transient increases in PIP3 that diminished 30 min after stimulation. Moreover, CHIP‐depleted C2C12s exhibited a concomitant reduction in the levels of phosphorylated AKT (Thr308), a signaling event that requires PIP3‐dependent translocation of AKT to the plasma membrane. The sustained PIP3 levels in wildtype C2C12s correlated with decreasing PTEN levels, a negative regulator of PIP3, at a time when CHIP and PTEN co‐immunoprecipitate. Conversely, a decrease in PTEN is not observed in CHIP‐depleted cells. Together, these data describe a novel role for CHIP in an insulin induced phosphorylation signaling cascade regulating microtubule polymerization necessary for glucose transporter translocation, thereby promoting glucose homeostasis and sensitivity to insulin.