Endoplasmic Reticulum Stress Activates Cleavage of CREBH to induce a Systemic Inflammatory Response

 Cell 124:587-599, 2006

Speaker: 羅苑菁                            Time: 2006/5/10 14:10~15:00

Commentator: 賴明德 老師                   Place: Room 601

Abstract:

ER stress is induced in the cell due to the accumulation of unfolded or misfolded proteins in the ER lumen. One of response to ER stress is the regulation of intramembrane proteolysis by ATF6. Previously, it was reported that CREBH, a liver-specific basic leucine zipper (b-Zip) transcription factor, shares significant homology with ATF6. However, the functions of CREBH are not clear. In this study, the authors observed that CREBH mRNA was induced by IL6 in murine H2.35 hepatoma cells. CREBH was cleaved by site-1 and site-2 proteases upon ER stress induction. Subsequently the N-terminal fragment of CREBH translocated to the nucleus and bound on the ER stress-response cis-acting element, the UPR element. In addition, the expression of C-reacting protein (CRP) and serum amyloid P-component (SAP) involved in the acute inflammatory response were down-regulated in CREBH -knockdown mice. Moreover, ER stress induction by tunicamycin activated both unfolding protein response (UPR) and acute inflammatory response in C57BL/6J mice. Interestingly, LPS and IL6 induced UPR and cleavage of CREBH. Furthermore, CREBH interacted with ATF6 as heterodimer, which synergistically activated the transcription of the CRP and SAP genes. Based on these results, the authors concluded that CREBH plays a critical role in activation of the acute inflammatory response.

Reference:

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2.      Omori, Y., et al. CREBH: a novel mammalian transcription factor belonging to the CREB/ATF family and functioning via the box-B element with a liver-specific expression. Nucleic Acids Research. 29:154-2162, 2001.