Linking the ER to Systemic Inflammatory Responses

Science's STKE  21 Feb 2006:
Vol. 2006, Issue 323, pp. tw70
DOI: 10.1126/stke.3232006tw70

Zhang et al. report a mechanism by which cleavage of a transmembrane protein in the endoplasmic reticulum (ER) can contribute to a systemic inflammatory response to ER stress (the presence of unfolded or misfolded proteins) or proinflammatory cytokines. CREBH is a member of a family of membrane-bound transcription factors that includes ATF6, a factor previously implicated in the unfolded protein response in the ER. These proteins undergo specific cleavage and then translocate to the nucleus, where they regulate gene expression. The authors used a viral expression system to induce expression of siRNAs to specifically inhibit expression of CREBH in mouse liver. CREBH was required for gene transcription associated with the inflammatory component of the innate immune system known as the acute phase response (APR). Response of target genes to interleukin 6 administered with interleukin-1β or LPS (bacterial lipopolysaccharide) was blunted in the absence of CREBH. Further analysis of transcriptional regulation of the genes encoding serum amyloid P-component (SAP) and C-reactive protein (CRP)--two components of the APR--showed that CREBH acted synergistically with ATF6 to regulate transcription. Concentrations of CRP in the blood are correlated with risk of heart attack. The authors note that their findings may lead to new therapeutic strategies by explaining a link from ER stress to stimulation of the acute inflammatory response and its associated pathology.

K. Zhang, X. Shen, J. Wu, K. Sakaki, T. Saunders, D. T. Rutkowski, S. H. Back, R. J. Kaufman, Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 124, 587-599 (2006). [PubMed]