Protein phosphatase 4 negatively regulates LPS cascade by inhibiting ubiquitination of TRAF6.
TRAF6 is an E3 ubiquitin ligase that transduces signals from members of the TLR/IL-1R family. Multiple molecules have been found to associate with TRAF6 and exert their functions in this pathway. Herein, by yeast two-hybrid screen using TRAF6 as bait, we identified PP4 as a potential TRAF6-interacting protein. PP4 physically interacted with TRAF6 and was recruited to TLR4 complex upon LPS stimulation. PP4 negatively regulated LPS-induced and TRAF6-mediated NF-kappaB activation by inhibiting the ubiquitination of TRAF6. LPS stimulation also induced the expression of PP4. Taken together, our findings suggest that PP4 is a negative feedback regulator of LPS/TLR4 pathway.
Chen
Lu
L
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei, PR China.
Dong
Wei
W
Zou
Tingting
T
Ouyang
Lu
L
He
Guoqing
G
Liu
Yingle
Y
Qi
Yipeng
Y
D000818:Animals; D002460:Cell Line; D025461:Feedback, Physiological; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D008070:Lipopolysaccharides; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D044767:Ubiquitin-Protein Ligases; D010749:Phosphoprotein Phosphatases; C080406:protein phosphatase 4