Protein phosphatase 4 negatively regulates LPS cascade by inhibiting ubiquitination of TRAF6☆

Abstract 

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-κB 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.

Abbreviations: TRAF6, tumor necrosis factor receptor-associated factor 6, TLR, toll-like receptor, IL, interleukin, NF-κB, nuclear factor-κB, LPS, lipopolysaccharide, MAPK, mitogen-activated protein kinase, JNK, c-Jun N-terminal kinase, MyD88, myeloid differentiation primary response gene 88, IRAK, IL-1 receptor-associated kinase, TAK1, transforming growth factor-β-activated kinase-1, TOLLIP, toll-interacting protein, SOCS, suppressor of cytokine signaling, IKK, IκB kinase, TNF, tumor necrosis factor, TAB, TAK1 binding protein, CSF, colony-stimulating factor, CYLD, cylindromatosis, TCR, T-cell receptor

Keywords: Protein phosphatase 4, Tumor necrosis factor receptor-associated factor 6, Lipopolysaccharide, Nuclear factor-κB, Ubiquitination