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.
Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Kezhong
K
Zhang
Xiaohua
X
Shen
Jun
J
Wu
Kenjiro
K
Sakaki
Thomas
T
Saunders
D Thomas
DT
Rutkowski
Sung Hoon
SH
Back
Randal J
RJ
Kaufman
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