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postgraduate thesis: Characterization of an orphan receptor : sub-cellular localization, ligand identification and cellular events for signaling activation of toll-like receptor 10

TitleCharacterization of an orphan receptor : sub-cellular localization, ligand identification and cellular events for signaling activation of toll-like receptor 10
Authors
Issue Date2015
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Yip, T. [葉慈灃]. (2015). Characterization of an orphan receptor : sub-cellular localization, ligand identification and cellular events for signaling activation of toll-like receptor 10. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5699962
AbstractToll-like receptors (TLRs) play key roles in innate immune recognition of pathogen-associated molecular patterns (PAMPs) of invading microbes. Among the ten TLR family members identified in humans, TLR10 remains an orphan receptor without known agonist or function. Recent studies have reported genetic polymorphisms of TLR10 in humans in association with diverse diseases, including inflammatory and respiratory diseases, but the mechanisms remain obscure. Lately, study has revealed that influenza virus infection increased TLR10 expression and demonstrated novel findings showing an involvement of TLR10 in innate immune sensing of viral infection leading to cytokine and interferon (IFN) induction, suggesting a role of TLR10 as a new innate immune sensor. However, some key questions regarding TLR10 remain unanswered. In this study, the sub-cellular localization, ligand, and cellular events for TLR10 signaling activation were investigated. Sub-cellular localization was studied using confocal microscopy and revealed that TLR10 was predominantly expressed intracellularly. They are vesicle bound receptors and majority of them were expressed in early or recycling endosomes. Using TLR10 over-expressing THP-1 cells, poly(I:C) induced IFN-β expression was found to be suppressed by TLR10, suggesting that dsRNA could be a ligand for TLR10 signaling to suppress IFN expression. Binding of poly(I:C) to TLR10 was found to be facilitated at acidic but not mildly alkaline pH, suggesting that TLR10 may sense its ligand within the acidic compartments such as endosomes. Upon poly(I:C) stimulation, adapter protein, myeloid differentiation primary response 88 (MyD88) was recruited to TLR10. A computational model of TLR10 revealed that TLR10 shares similar structural features with other nucleic acid sensing TLRs. Proteolytic modification was needed and partially mediated by cathepsins for TLR10 signal activation. Taken together, the data arising from this study provides important novel information for understanding the role of TLR10 in disease pathogenesis and opens a new area in innate immunity.
DegreeMaster of Philosophy
SubjectCell receptors
Dept/ProgramPublic Health
Persistent Identifierhttp://hdl.handle.net/10722/223025

 

DC FieldValueLanguage
dc.contributor.authorYip, Tsz-fung-
dc.contributor.author葉慈灃-
dc.date.accessioned2016-02-17T23:14:34Z-
dc.date.available2016-02-17T23:14:34Z-
dc.date.issued2015-
dc.identifier.citationYip, T. [葉慈灃]. (2015). Characterization of an orphan receptor : sub-cellular localization, ligand identification and cellular events for signaling activation of toll-like receptor 10. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5699962-
dc.identifier.urihttp://hdl.handle.net/10722/223025-
dc.description.abstractToll-like receptors (TLRs) play key roles in innate immune recognition of pathogen-associated molecular patterns (PAMPs) of invading microbes. Among the ten TLR family members identified in humans, TLR10 remains an orphan receptor without known agonist or function. Recent studies have reported genetic polymorphisms of TLR10 in humans in association with diverse diseases, including inflammatory and respiratory diseases, but the mechanisms remain obscure. Lately, study has revealed that influenza virus infection increased TLR10 expression and demonstrated novel findings showing an involvement of TLR10 in innate immune sensing of viral infection leading to cytokine and interferon (IFN) induction, suggesting a role of TLR10 as a new innate immune sensor. However, some key questions regarding TLR10 remain unanswered. In this study, the sub-cellular localization, ligand, and cellular events for TLR10 signaling activation were investigated. Sub-cellular localization was studied using confocal microscopy and revealed that TLR10 was predominantly expressed intracellularly. They are vesicle bound receptors and majority of them were expressed in early or recycling endosomes. Using TLR10 over-expressing THP-1 cells, poly(I:C) induced IFN-β expression was found to be suppressed by TLR10, suggesting that dsRNA could be a ligand for TLR10 signaling to suppress IFN expression. Binding of poly(I:C) to TLR10 was found to be facilitated at acidic but not mildly alkaline pH, suggesting that TLR10 may sense its ligand within the acidic compartments such as endosomes. Upon poly(I:C) stimulation, adapter protein, myeloid differentiation primary response 88 (MyD88) was recruited to TLR10. A computational model of TLR10 revealed that TLR10 shares similar structural features with other nucleic acid sensing TLRs. Proteolytic modification was needed and partially mediated by cathepsins for TLR10 signal activation. Taken together, the data arising from this study provides important novel information for understanding the role of TLR10 in disease pathogenesis and opens a new area in innate immunity.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.lcshCell receptors-
dc.titleCharacterization of an orphan receptor : sub-cellular localization, ligand identification and cellular events for signaling activation of toll-like receptor 10-
dc.typePG_Thesis-
dc.identifier.hkulb5699962-
dc.description.thesisnameMaster of Philosophy-
dc.description.thesislevelMaster-
dc.description.thesisdisciplinePublic Health-
dc.description.naturepublished_or_final_version-

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