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Adaptive suppression of the ATF4–CHOP branch of the unfolded protein response by toll-like receptor signalling

Abstract

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-2α, which are upstream of CHOP, but phospho-eIF-2α 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.

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Figure 1: Pretreatment of macrophages with low dose LPS selectively suppresses the ATF4 –CHOP branch of the UPR.
Figure 2: The ability of low dose LPS to suppress tunicamycin-induced CHOP is dependent on the TRIF branch of TLR signalling.
Figure 3: LPS treatment of tunicamycin-treated mice suppresses CHOP expression in splenic macrophages.
Figure 4: LPS treatment of tunicamycin-treated mice suppresses renal tubular and hepatic CHOP induction, renal dysfunction, and hepatosteatosis.
Figure 5: Protection from tunicamycin-induced renal dysfunction and hepatosteatosis by pretreatment with low dose LPS is due to suppression of CHOP.

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Acknowledgements

This work was supported by a German Research Foundation Grant (B.D.), NIH grants HL75662, HL57560 (I.T.), DK47119 and ES08681( D.R.). We thank Alice Prince and Vincent Racaniello (Columbia University) for helpful discussions related to the high-dose LPS mouse experiments and biological effects of TRIF signalling, respectively.

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C.W., D.C., J.A. and B.D. performed the experiments and assisted with planning the experiments, data analysis and writing the manuscript; H.H. and K.A.F. assisted with planning the experiments and data analysis; D.R. assisted with planning the experiments, data analysis, and writing the manuscript; I.T. coordinated the project and assisted with planning the experiments, data analysis, and writing the manuscript. All authors discussed the results and manuscript text.

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Correspondence to Ira Tabas.

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Woo, C., Cui, D., Arellano, J. et al. Adaptive suppression of the ATF4–CHOP branch of the unfolded protein response by toll-like receptor signalling. Nat Cell Biol 11, 1473–1480 (2009). https://doi.org/10.1038/ncb1996

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