6533b837fe1ef96bd12a334e
RESEARCH PRODUCT
Adaptive suppression of the ATF4–CHOP branch of the unfolded protein response by toll-like receptor signalling
David RonDongying CuiBernhard DorweilerBernhard DorweilerKatherine A. FitzgeraldConnie W.h. WooHeather P. HardingJerry ArellanoIra Tabassubject
LipopolysaccharidesBiologyCHOPEndoplasmic ReticulumArticleMice03 medical and health sciences0302 clinical medicineStress Physiologicalhemic and lymphatic diseasesAnimalsHumansCells Cultured030304 developmental biologyMice Knockout0303 health sciencesToll-like receptorEndoplasmic reticulumToll-Like ReceptorsATF4Cell BiologyActivating Transcription Factor 4Cell biologyMice Inbred C57BLAdaptor Proteins Vesicular TransportTRIF030220 oncology & carcinogenesisUnfolded Protein ResponseUnfolded protein responseTLR4biological phenomena cell phenomena and immunitySignal transductionTranscription Factor CHOPSignal Transductiondescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2009-10-25 | Nature Cell Biology |