Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response

Cell. 2006 Feb 10;124(3):587-99. doi: 10.1016/j.cell.2005.11.040.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Binding Sites / genetics
  • C-Reactive Protein / metabolism
  • Cyclic AMP Response Element-Binding Protein / chemistry
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Cytokines / metabolism
  • DNA / genetics
  • DNA / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Female
  • Fetus / metabolism
  • Inflammation / etiology*
  • Inflammation / metabolism*
  • Inflammation Mediators / metabolism
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Pregnancy
  • Proprotein Convertases / metabolism
  • RNA Interference
  • Serine Endopeptidases / metabolism
  • Serum Amyloid P-Component / metabolism

Substances

  • Creb3l3 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Cytokines
  • Inflammation Mediators
  • Peptide Fragments
  • Serum Amyloid P-Component
  • C-Reactive Protein
  • DNA
  • Proprotein Convertases
  • Serine Endopeptidases
  • membrane-bound transcription factor peptidase, site 1