The Role of Glucosamine-Induced ER Stress in Diabetic Atherogenesis

Figure 1

The unfolded protein response to endoplasmic reticulum stress. ER stress occurs when the capacity of the ER to process/fold proteins is exceeded by the load of nascent proteins entering the ER. The function of the UPR is to reestablish ER homeostasis by decreasing protein flux into the ER (translation block) while increasing the folding capacity of the ER (increased chaperone expression). Conditions of ER stress lead to the dissociation of ER chaperone GRP78 from the trans-ER-membrane signaling factors PERK, IRE1, and ATF6, resulting in their activation. Activated PERK phosphorylates and inhibits the activity of eIF2α, an essential factor in general protein translation. PERK is also involved with the downstream activation of transcription factors including ATF4 and GADD153. Activated IRE1 assists in the alternative splicing of XBP-1 resulting in the translation of a transcription factor, XBP-1, which is involved in upregulation of the expression of ER chaperones. Activated ATF6 translocates to the Golgi where proteases S1P and S2P release an N-terminal transcription activation domain that works in concert with XBP-1 to upregulate ER chaperone expression.