title: ER stress stimulates production of the key antimicrobial peptide, cathelicidin, by forming a previously unidentified intracellular S1P signaling complex.
abstract: We recently identified a previously unidentified sphingosine-1-phosphate (S1P) signaling mechanism that stimulates production of a key innate immune element, cathelicidin antimicrobial peptide (CAMP), in mammalian cells exposed to external perturbations, such as UVB irradiation and other oxidative stressors that provoke subapoptotic levels of endoplasmic reticulum (ER) stress, independent of the well-known vitamin D receptor-dependent mechanism. ER stress increases cellular ceramide and one of its distal metabolites, S1P, which activates NF-κB followed by C/EBPα activation, leading to CAMP production, but in a S1P receptor-independent fashion. We now show that S1P activates NF-κB through formation of a previously unidentified signaling complex, consisting of S1P, TRAF2, and RIP1 that further associates with three stress-responsive proteins; i.e., heat shock proteins (GRP94 and HSP90α) and IRE1α. S1P specifically interacts with the N-terminal domain of heat shock proteins. Because this ER stress-initiated mechanism is operative in both epithelial cells and macrophages, it appears to be a universal, highly conserved response, broadly protective against diverse external perturbations that lead to increased ER stress. Finally, these studies further illuminate how ER stress and S1P orchestrate critical stress-specific signals that regulate production of one protective response by stimulating production of the key innate immune element, CAMP.
authors.affiliation: Department of Dermatology, School of Medicine, University of California, San Francisco, CA 94158; Northern California Institute for Research and Education, Veterans Affairs Medical Center, San Francisco, CA 94121;
authors.forename: Kyungho
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Biochemistry, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan;
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ikushiro
authors.affiliation: Radiation Research Division, Korea Atomic Energy Research Institute, Jeongeup 580-185, Republic of Korea;
authors.forename: Ho Seong
authors.identifier: http://orcid.org/0000-0002-7103-1344
authors.initials: HS
authors.lastname: Seo
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 361-763, Republic of Korea;
authors.forename: Kyong-Oh
authors.initials: KO
authors.lastname: Shin
authors.affiliation: Department of Dermatology, School of Medicine, University of California, San Francisco, CA 94158; Northern California Institute for Research and Education, Veterans Affairs Medical Center, San Francisco, CA 94121;
authors.forename: Young Il
authors.initials: YI
authors.lastname: Kim
authors.affiliation: Northern California Institute for Research and Education, Veterans Affairs Medical Center, San Francisco, CA 94121; Department of Endocrinology, School of Medicine, University of California, San Francisco, CA 94121.
authors.forename: Jong Youl
authors.initials: JY
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 361-763, Republic of Korea;
authors.forename: Yong-Moon
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan;
authors.forename: Takato
authors.initials: T
authors.lastname: Yano
authors.affiliation: Department of Dermatology, School of Medicine, University of California, San Francisco, CA 94158; Northern California Institute for Research and Education, Veterans Affairs Medical Center, San Francisco, CA 94121;
authors.forename: Walter M
authors.initials: WM
authors.lastname: Holleran
authors.affiliation: Department of Dermatology, School of Medicine, University of California, San Francisco, CA 94158; Northern California Institute for Research and Education, Veterans Affairs Medical Center, San Francisco, CA 94121;
authors.forename: Peter
authors.initials: P
authors.lastname: Elias
authors.affiliation: Department of Dermatology, School of Medicine, University of California, San Francisco, CA 94158; Northern California Institute for Research and Education, Veterans Affairs Medical Center, San Francisco, CA 94121; Yoshikazu.Uchida@ucsf.edu.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Uchida
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D054804:Cathelicidins; D000099157:Sphingosine Kinase
chemical_list: D023181:Antimicrobial Cationic Peptides; D006360:Heat-Shock Proteins; D008246:Lysophospholipids; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D016601:RNA-Binding Proteins; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D047992:TNF Receptor-Associated Factor 2; D054804:Cathelicidins; D000099157:Sphingosine Kinase; C119724:AGFG1 protein, human; C060506:sphingosine 1-phosphate
keywords: ER stress; cathelicidin; heat shock protein 90; innate immunity; sphingosine-1-phosphate