title: Distinct Roles for APPL1 and APPL2 in Regulating Toll-like Receptor 4 Signaling in Macrophages.
abstract: Macrophages are activated by contact with pathogens to mount innate immune defenses against infection. Toll-like receptor 4 (TLR4) at the macrophage surface recognizes and binds bacterial lipopolysaccharide (LPS), setting off signaling and transcriptional events that lead to the secretion of pro- and anti-inflammatory cytokines; these in turn control inflammatory and antimicrobial responses. Although the complex regulatory pathways downstream of TLR4 have been extensively studied, further molecules critical for modulating the resulting cytokine outputs remain to be characterized. Here we establish potential roles for APPL1 and 2 signaling adaptors as regulators of LPS/TLR4-induced signaling, transcription, and cytokine secretion. APPL1 and 2 are differentially localized to distinct signaling-competent membrane domains on the surface and in endocytic compartments of LPS-activated macrophages. By depleting cells of each adaptor respectively we show separate and opposing functions for APPL1 and 2 in Akt and MAPK signaling. Specifically, APPL2 has a dominant role in nuclear translocation of NF-KB p65 and it serves to constrain the secretion of pro- and anti-inflammatory cytokines. The APPLs, and in particular APPL2, are thus revealed as adaptors with important capacity to modulate inflammatory responses mounted by LPS/TLR4 during infection.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Yeo
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Wall
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
authors.forename: Lin
authors.initials: L
authors.lastname: Luo
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Condon
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stow
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D018929:Cell Culture Techniques; D002460:Cell Line; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C510733:Appl1 protein, mouse; D016207:Cytokines; C000602283:DCC-interacting protein 13-beta, mouse; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA
keywords: cytokines; macrophage; receptors; signaling adaptors