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The endoplasmic reticulum (ER) is an essential site responsible for protein synthesis and maturation. Newly synthesized polypeptide chains enter the ER through a peptide translocon, and undergo maturation processes such as cleavage, glycosylation, disulfide bond formation, folding and assembly. Perturbation of the protein maturation processes, caused by hypoxia, viral and bacterial infections, inhibition of protein glycosylation or disulfide bond formation, results in accumulation of unfolded and misfolded proteins in the lumen of the ER. This condition is known as ER stress. Increased rate of protein synthesis and unbalanced protein folding capacity of the ER can also lead to ER stress. Studies over the past decade have demonstrated that ER stress can be induced in a variety of cells and tissues when exposed to physiological and pathological stresses, and plays an important role in cell injury and disease development in cancer, diabetes, and neurodegenerative and vascular diseases (for review, please see1, 2). To protect ER function and ensure the fidelity of protein folding, eukaryotic cells have evolved an adaptive mechanism named unfolded protein response (UPR). The UPR consists of three branches, which can be activated by any given ER stress event, but timing and sequence of the activation may differ.3,4 Activation of the UPR enhances protein folding capacity and reduces ER stress by inducing ER chaperones. These ER resident molecular chaperones are important for post-translational modification, assembly and quality control of newly synthesized proteins.5-7 In this review, we summarize recent research progress on p58IPK, an ER stress-regulated chaperone, and discuss its role in signaling pathways of ER stress, apoptosis and inflammation.