A PTP4A3 peptide PIMAP39 modulates TNF-alpha levels and endotoxic shock.
Lipopolysaccharide (LPS) stimulation of macrophages initiates intracellular signaling pathways leading to activation of MAPK and its subsequent influence on cytokine production. We recently identified a LITAF-STAT6(B) complex regulated by p38 MAPK in response to LPS stimulation. However, the LPS-induced cascade in the p38/LITAF/TNF signaling pathway remains unclear. Here, we identified PTP4A3, a protein tyrosine phosphotase, as a novel negative regulator of LPS-induced LITAF/TNF-alpha production. PTP4A3 exerts its negative role by dephosphorylating p38 alpha MAPK in response to LPS stimulation of primary macrophages. PTP4A3 expression is upregulated in primary macrophages. Further structure-function analysis revealed that a unique short peptide (PIMAP39) derived from PTP4A3 is capable of mimicking the functionality of full-length PTP4A3 to selectively dephosphorylate p38 alpha and indirectly suppress LPS-induced LITAF-STAT6B complex when it is translocated from the cytoplasmic region to the nucleus of the cell. Treatment of mice with PIMAP39 significantly attenuates the severity of adverse host responses to LPS stimulation, and in some cases provides complete resistance to a lethal dose of LPS due to suppression of TNF-alpha production. All together, these results reveal a previously unrecognized role for the PTP4A3 pathway in response to LPS.
Tang
Xiaoren
X
Department of Periodontology and Oral Biology, Boston University Goldman School of Dental Medicine, Boston, MA 02118, USA.
Woodward
Timothy
T
Amar
Salomon
S
D000818:Animals; D004268:DNA-Binding Proteins; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D048308:Mitogen-Activated Protein Kinase 14 / Q000276:immunology; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D010455:Peptides / Q000276:immunology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000276:immunology*; D012772:Shock, Septic / Q000201:enzymology / Q000276:immunology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides; C492727:Litaf protein, mouse; D009687:Nuclear Proteins; D010455:Peptides; C111534:Ptp4a3 protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D048308:Mitogen-Activated Protein Kinase 14; D017027:Protein Tyrosine Phosphatases