title: A phosphoproteomic study reveals shp-1 cleavage reprograms LPS signaling via a PI-3K/NF-κB and mTORC1 related mechanism.
abstract: The reprogrammed lipopolysaccharide (LPS) pathway has been reported to render patients more susceptible to the development of post-traumatic multiple organ dysfunction syndrome (MODS). To facilitate thorough understanding of this mechanism, a phosphoproteomic study was utilized to screen the potential signaling molecules. Interestingly, a truncated form of Src homology 2-domain-containing tyrosine phosphatase 1 (shp-1) emerged in human THP-1 macrophages sequentially treated with H2O2 and LPS and not with either of the treatments alone. Subsequent immunoblot analysis confirmed the cleavage of shp-1 and reduction of shp-1 activity in rat alveolar macrophages, mast cells, and neutrophils. Mechanistically, calpain is essential but not sufficient for shp-1 cleavage. In addition, shp-1 cleavage renders the activation of phosphatidylinositol 3-kinase (PI-3K)/nuclear factor-κB (NF-κB) and mechanistic target of rapamycin complex 1 (mTORC1) in macrophages, resulting in enhanced cytokine induced neutrophil chemoattractant (CINC) secretion, which is critical for neutrophil recruitment in MODS. On the other hand, shp-1 cleavage results in the activation of PI-3K/Akt, enhancing the survival of neutrophils. Collectively, these results highlight the cleavage of shp-1 as a critical event in reprogramming LPS pathway to promote both neutrophil recruitment and survival and provide a novel mechanistic framework for the investigation of the post-traumatic MODS.
authors.affiliation: Department of Thoracic Surgery, General Hospital of Guangzhou Military Command of Chinese People's Liberation Army, Guangzhou 510010, China.
authors.forename: Enwu
authors.initials: E
authors.lastname: Xu
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: landj@smu.edu.cn.
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Intensive Care Unit, The 309th Hospital of People's Liberation Army, Beijing 100091, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Ke
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Shenqiu
authors.initials: S
authors.lastname: Luo
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: zzp@smu.edu.cn.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Zou
mesh_terms: D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods; D020543:Proteome / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D020543:Proteome; D058570:TOR Serine-Threonine Kinases
keywords: MODS; PI-3K; Phosphoproteome; Shp-1; mTORC1