Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling.
The endoplasmic reticulum (ER) unfolded protein response (UPR) restores equilibrium to the ER, but prolonged expression of the UPR effector CHOP (GADD153) is cytotoxic. We found that CHOP expression induced by ER stress was suppressed by prior engagement of toll-like receptor (TLR) 3 or 4 through a TRIF-dependent pathway. TLR engagement did not suppress phosphorylation of PERK or eIF-2alpha, which are upstream of CHOP, but phospho-eIF-2alpha failed to promote translation of the CHOP activator ATF4. In mice subjected to systemic ER stress, pretreatment with low dose lipopolysaccharide (LPS), a TLR4 ligand, suppressed CHOP expression and apoptosis in splenic macrophages, renal tubule cells and hepatocytes, and prevented renal dysfunction and hepatosteatosis. This protective effect of LPS did not occur in Trif(-/-) mice or in wild-type mice in which CHOP expression was genetically restored. Thus, TRIF-mediated signals from TLRs selectively attenuate translational activation of ATF4 and its downstream target gene CHOP. We speculate that this mechanism evolved to promote survival of TLR-expressing cells that experience prolonged levels of physiological ER stress in the course of the host response to invading pathogens.
Department of Medicine, Columbia University, New York, NY 10032, USA.
Connie W
CW
Woo
Dongying
D
Cui
Jerry
J
Arellano
Bernhard
B
Dorweiler
Heather
H
Harding
Katherine A
KA
Fitzgerald
David
D
Ron
Ira
I
Tabas
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D013312:Stress, Physiological; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000172:deficiency / Q000378:metabolism*; D056811:Unfolded Protein Response
D051701:Activating Transcription Factor 4; D033942:Adaptor Proteins, Vesicular Transport; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D051742:Transcription Factor CHOP; C497109:ATF4 protein, human; C081452:Atf4 protein, mouse; C497249:DDIT3 protein, human; C497250:Ddit3 protein, mouse; C476286:Ticam1 protein, mouse