Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response.
Regulated intramembrane proteolysis (RIP) of endoplasmic reticulum (ER) membrane-anchored transcription factors is known to maintain sterol homeostasis and to mediate the unfolded protein response (UPR). Here, we identified CREBH as a RIP-regulated liver-specific transcription factor that is cleaved upon ER stress and required to activate expression of acute phase response (APR) genes. Proinflammatory cytokines increase expression of ER membrane-anchored CREBH. In response to ER stress, CREBH is cleaved by site-1 and site-2 proteases to liberate an amino-terminal fragment that transits to the nucleus to activate transcription of the genes encoding serum amyloid P-component (SAP) and C-reactive protein (CRP). Proinflammatory cytokines and lipopolysaccharide activate the UPR and induce cleavage of CREBH in the liver in vivo. Together, our studies delineate a molecular mechanism for activation of an ER-localized transcription factor, CREBH, and reveal an unprecedented link by which ER stress initiates an acute inflammatory response.
Zhang
Kezhong
K
Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Shen
Xiaohua
X
Wu
Jun
J
Sakaki
Kenjiro
K
Saunders
Thomas
T
Rutkowski
D Thomas
DT
Back
Sung Hoon
SH
Kaufman
Randal J
RJ
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002097:C-Reactive Protein / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D005333:Fetus / Q000378:metabolism; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D043484:Proprotein Convertases / Q000378:metabolism; D034622:RNA Interference; D012697:Serine Endopeptidases / Q000378:metabolism; D000683:Serum Amyloid P-Component / Q000378:metabolism
C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D018836:Inflammation Mediators; D010446:Peptide Fragments; D000683:Serum Amyloid P-Component; D002097:C-Reactive Protein; D004247:DNA; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1