The E3 ubiquitin ligase Nedd4-2 may play a protective role against ER stress-induced insulin resistance in the liver  — ASN Events
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The E3 ubiquitin ligase Nedd4-2 may play a protective role against ER stress-induced insulin resistance in the liver  (#256)

Hao Wang 1 , Ruoqiong Sun 1 , Daria Camera 1 , Xiaoyi Zeng 1 , Eunjung Jo 1 , Juan Molero 1 , Jiming Ye 1
  1. RMIT University, Bundoora, VIC, Australia

Accumulation of unfolded or misfolded proteins is a major cause of endoplasmic reticulum (ER) stress which contributes to insulin resistance in the liver. Recent studies suggest that ER stress-induced insulin resistance may involve the interactions between ER stress and protein degradation pathways including autophagy and ubiquitin-proteasome system (UPS) (Casas, et al. 2007, Wang, et al. 2015). The present study investigated the role of the E3 ubiquitin ligase neural precursor cell expressed developmentally down-regulated protein 4-2 (Nedd4-2) in relation to ER stress and autophagy. We found that mice fed a high-fructose diet showed significant increases in Nedd4-2 expression and ER stress in the liver associated with insulin resistance. Similar increases in Nedd4-2 and ER stress were observed in mouse embryonic fibroblasts in response to the ER stress inducers tunicamycin and thapsigargin. In order to examine the role of Nedd4-2 in ER stress, we transfected HEK293 cells to overexpress or knockdown Nedd4-2. The results showed overexpression of Nedd4-2 reduced ER stress and this was associated with an increase in autophagy and protein ubiquitination. In contrast, knockdown of Nedd4-2 in HEK293 cells increased ER stress and suppressed autophagy. Consistent with this, we found Nedd4-2 deficiency (Nedd4-2 +/-) also displayed a suppression of autophagy in the liver. As the IRE1/XBP1 branch is activated by high-fructose feeding in the liver of mice at the very early stage (Sun, et al. 2015), we further investigated the role of XBP1 in Nedd4-2 expression in HEK293 cells. The results showed that knockdown of XBP1 by siRNAs reduced Nedd4-2 expression. Our findings suggest that Nedd4-2 may play a protective role against ER stress-induced insulin resistance in the liver by activating protein degradation pathways and XBP1 appears to be a regulator for Nedd4-2 expression. 

  1. Casas, S., et al. (2007). "Impairment of the ubiquitin-proteasome pathway is a downstream endoplasmic reticulum stress response induced by extracellular human islet amyloid polypeptide and contributes to pancreatic beta-cell apoptosis." Diabetes 56(9): 2284-2294.
  2. Wang, H., et al. (2015). "Restoration of autophagy alleviates hepatic ER stress and impaired insulin signalling transduction in high fructose-fed male mice." Endocrinology 156(1): 169-181
  3. Sun, R. Q., et al. (2015). "IRE1 impairs insulin signaling transduction of fructose-fed mice via JNK independent of excess lipid." Biochim Biophys Acta 1852(1): 156-165.