title: TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin.
abstract: Regulating the transcription, translation and secretion of cytokines is crucial for controlling the appropriate balance of inflammation. Here we report that the sorting receptor sortilin plays a key role in cytokine production. We observed interactions of sortilin with multiple cytokines including IFN-α, and sortilin depletion in plasmacytoid dendritic cells (pDCs) led to a reduction of IFN-α secretion, suggesting a pivotal role of sortilin in the exocytic trafficking of IFN-α in pDCs. Moreover, sortilin mRNA was degraded posttranscriptionally upon stimulation with various TLR ligands. Poly-rC-binding protein 1 (PCBP1) recognized the C-rich element (CRE) in the 3' UTR of sortilin mRNA, and depletion of PCBP1 enhanced the degradation of sortilin transcripts, suggesting that PCBP1 can act as a trans-acting factor to stabilize sortilin transcripts. The nucleotide-binding ability of PCBP1 was impaired by zinc ions and alterations of intracellular zinc affect sortilin expression. PCBP1 may therefore control the stability of sortilin transcripts by sensing intracellular zinc levels. Collectively, our findings provide insights into the posttranslational regulation of cytokine production through the posttranscriptional control of sortilin expression by TLR signals.
authors.affiliation: Department of Immunology, Kanazawa Medical University, Kahoku Uchinada, Ishikawa, 920-0293, JAPAN.|Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Yabe-Wada
authors.affiliation: Department of Immunology, Kanazawa Medical University, Kahoku Uchinada, Ishikawa, 920-0293, JAPAN.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Matsuba
authors.affiliation: Department of Immunology, Kanazawa Medical University, Kahoku Uchinada, Ishikawa, 920-0293, JAPAN.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Sato
authors.affiliation: Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Mikita
authors.initials: M
authors.lastname: Suyama
authors.affiliation: Department of Advanced Medical Initiatives, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ohkawa
authors.affiliation: Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo, Sendai 980-8575, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takai
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Shi
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Philpott
authors.affiliation: Department of Immunology, Kanazawa Medical University, Kahoku Uchinada, Ishikawa, 920-0293, JAPAN.
authors.forename: Akira
authors.initials: A
authors.lastname: Nakamura
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D000818:Animals; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology*; D051379:Mice; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology*; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016898:Interferon-alpha; D051193:Toll-Like Receptors; D000099183:Sortilin