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

Zhang, K. et al. Cell 124, 587-599 (2006)

Student: 黃薇靜                                            Time: 15:00-16:00, Dec. 6, 2006

Commentator: 徐麗君 老師                         Place: Room 601

Abstract

Regulated intramembrane proteolysis (RIP) of endoplasmic reticulum (ER) membrane-anchored transcription factors is the process in ER stress by which transmembrane proteins are cleaved to release cytosolic domains that transit into the nucleus to regulate gene transcription such as unfolded protein response (UPR)¹. CREBH is reported as a hepatocyte-specific transcription factor belonging to the cyclic AMP response element binding protein transcription factor (CREB/ATF) family². It is a transmembrane protein that contains a cytosolic transcription activation domain, a basic leucine zipper domain in close proximity to a hydrophobic transmembrane domain, and a domain that resides in the ER lumen. In this study³, the molecular mechanisms of CREBH activation in response to proinflammatory cytokines and ER stress and its biological role in activation of an acute inflammatory response are investigated. The expression of CREBH was found in fetal liver during embryogenesis and was increased by IL-6 stimulation. The authors identified CREBH as a RIP-regulated liver-specific transcription factor that is cleaved upon ER stress by site-1 and site-2 proteases to release its N-terminal fragment followed by nuclear entry. Upon the stimulation of proinflammatory cytokines, lipopolysaccharide, and ER stress, CREBH was required to activate expression of acute phase response genes encoding serum amyloid P-component and C-reactive protein as demonstrated in vivo using CREBH knockdown mice and in vitro using primary hepatocytes. Furthermore, proinflammatory cytokines and LPS induced UPR expression and CREBH cleavage in liver. Taken together, these results demonstrate that ER stress induces an inflammatory response in liver through the activation of ER-localized transcription factor CREBH.

References

1.   Brown, M. S. et al. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100, 391-398 (2000).

2.   Omori, Y. et al. CREB-H: 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 Res. 29, 2154-2162 (2001).

3.   Zhang, K. et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 124, 587-599 (2006)