The CYR61/CTGF/NOV (CCN) family members induce endoplasmic reticulum stress and unfolded protein response

Background: The endoplasmic reticulum (ER) is the site of synthesis and folding of secreted membrane-bound and diverse organelle-targeted proteins. This process requires several factors, including ATP, Ca2+ and an oxidizing environment for proper disulphide-bond formation. The ER is sensitive to stress factors that perturb cellular energy levels, cellular redox state, or intracellular Ca2+ content. As a consequence, these alterations reduce the protein folding capacity of the ER leading to accumulation and aggregation of unfolded proteins ending an orchestrated response which is known as unfolded protein response (UPR). We and others have shown that matricellular proteins of the CCN (CYR61, CTGF, NOV) family play essential roles in extracellular matrix signaling and turnover [1 – 3]. They share a similar architecture and contain a high content of cysteine residues. Previously, we have shown that large quantities of CCN1/CYR61 induce reactive oxygen species formation in portal myofibroblasts and ER stress in hepatic stellate cells (HSC) [1, 2].