NDLI: Endosomal localization of TLR8 confers distinctive proteolytic processing on human myeloid cells.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Funami, Kenji Matsumoto, Misako Ishii, Noriko Seya, Tsukasa Tatematsu, Megumi
Description	Country affiliation: Japan Author Affiliation: Ishii N ( Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.); Funami K ( Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.); Tatematsu M ( Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.); Seya T ( Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.); Matsumoto M ( Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan matumoto@pop.med.hokudai.ac.jp.)
Abstract	Nucleic acid-sensing TLRs are involved in both antimicrobial immune responses and autoimmune inflammation. TLR8 is phylogenetically and structurally related to TLR7 and TLR9, which undergo proteolytic processing in the endolysosomes to generate functional receptors. Recent structural analyses of human TLR8 ectodomain and its liganded form demonstrated that TLR8 is also cleaved, and both the N- and C-terminal halves contribute to ligand binding. However, the structures and ssRNA recognition mode of endogenous TLR8 in human primary cells are largely unknown. In this study, we show that proteolytic processing of TLR8 occurs in human monocytes and macrophages in a different manner compared with TLR7/9 cleavage. The insertion loop between leucine-rich repeats 14 and 15 in TLR8 is indispensable for the cleavage and stepwise processing that occurs in the N-terminal fragment. Both furin-like proprotein convertase and cathepsins contribute to TLR8 cleavage in the early/late endosomes. TLR8 recognizes viral ssRNA and endogenous RNA, such as microRNAs, resulting in the production of proinflammatory cytokines. Hence, localization sites of the receptors are crucial for the nucleic acid-sensing mode and downstream signaling.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	10
Volume Number	193
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2014-11-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Endosomes Metabolism Macrophages Monocytes Rna, Viral Toll-like Receptor 8 Amino Acid Sequence Cathepsins Gene Expression Hek293 Cells Ligands Lysosomes Chemistry Cytology Micrornas Molecular Sequence Data Primary Cell Culture Proprotein Convertase 1 Protein Binding Protein Structure, Secondary Protein Structure, Tertiary Proteolysis Signal Transduction Toll-like Receptor 7 Genetics Toll-like Receptor 9 Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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