title: Protein phosphatase 2A catalytic subunit α plays a MyD88-dependent, central role in the gene-specific regulation of endotoxin tolerance.
abstract: MyD88, the intracellular adaptor of most TLRs, mediates either proinflammatory or immunosuppressive signaling that contributes to chronic inflammation-associated diseases. Although gene-specific chromatin modifications regulate inflammation, the role of MyD88 signaling in establishing such epigenetic landscapes under different inflammatory states remains elusive. Using quantitative proteomics to enumerate the inflammation-phenotypic constituents of the MyD88 interactome, we found that in endotoxin-tolerant macrophages, protein phosphatase 2A catalytic subunit α (PP2Ac) enhances its association with MyD88 and is constitutively activated. Knockdown of PP2Ac prevents suppression of proinflammatory genes and resistance to apoptosis. Through site-specific dephosphorylation, constitutively active PP2Ac disrupts the signal-promoting TLR4-MyD88 complex and broadly suppresses the activities of multiple proinflammatory/proapoptotic pathways as well, shifting proinflammatory MyD88 signaling to a prosurvival mode. Constitutively active PP2Ac translocated with MyD88 into the nuclei of tolerant macrophages establishes the immunosuppressive pattern of chromatin modifications and represses chromatin remodeling to selectively silence proinflammatory genes, coordinating the MyD88-dependent inflammation control at both signaling and epigenetic levels under endotoxin-tolerant conditions.
authors: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Ling
authors: L
authors: Xie
authors: Cui
authors: C
authors: Liu
authors: Li
authors: L
authors: Wang
authors: Harsha P
authors: HP
authors: Gunawardena
authors: Yanbao
authors: Y
authors: Yu
authors: Ruyun
authors: R
authors: Du
authors: Debra J
authors: DJ
authors: Taxman
authors: Penggao
authors: P
authors: Dai
authors: Zhen
authors: Z
authors: Yan
authors: Jing
authors: J
authors: Yu
authors: Stephen P
authors: SP
authors: Holly
authors: Leslie V
authors: LV
authors: Parise
authors: Yisong Y
authors: YY
authors: Wan
authors: Jenny P
authors: JP
authors: Ting
authors: Xian
authors: X
authors: Chen
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D044127:Epigenesis, Genetic / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D002843:Chromatin; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D020543:Proteome; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D054648:Protein Phosphatase 2