A naturally occurring variant in human TLR9, P99L, is associated with loss of CpG oligonucleotide responsiveness

• Verfasst von: Kubarenko, Andriy [VerfasserIn]
• Verfasst von: Ranjan, Satish [VerfasserIn]
• Verfasst von: Rautanen, Anna [VerfasserIn]
• Verfasst von: Mills, Tara C. [VerfasserIn]
• Verfasst von: Wong, Sunny [VerfasserIn]
• Verfasst von: Vannberg, Fredrik [VerfasserIn]
• Verfasst von: Neumaier, Michael [VerfasserIn]
• Verfasst von: Bekeredjian-Ding, Isabelle [VerfasserIn]
• Verfasst von: Hill, Adrian V. S. [VerfasserIn]
• Verfasst von: Ahmad-Nejad, Parviz [VerfasserIn]
• Verfasst von: Weber, Alexander N. R. [VerfasserIn]
• Titel: A naturally occurring variant in human TLR9, P99L, is associated with loss of CpG oligonucleotide responsiveness
• Verf.angabe: Andriy V. Kubarenko, Satish Ranjan, Anna Rautanen, Tara C. Mills, Sunny Wong, Fredrik Vannberg, Michael Neumaier, Isabelle Bekeredjian-Ding, Adrian V.S. Hill, Parviz Ahmad-Nejad, and Alexander N.R. Weber
• E-Jahr: 2010
• Jahr: 14 September 2010
• Umfang: 9 S.
• Fussnoten: Online verfügbar 14 September 2010, Artikelversion 4 Januar 2021 ; Gesehen am 06.03.2023
• Titel Quelle: Enthalten in: The journal of biological chemistry
• Ort Quelle: Bethesda, Md. : ASBMB Publications, 1905
• Jahr Quelle: 2010
• Band/Heft Quelle: 285(2010), 47 vom: Sept., Seite 36486-36494
• ISSN Quelle: 1083-351X
• DOI: doi:10.1074/jbc.M110.117200
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Computer Modeling
• Sach-SW: CpG-Oligonucleotide
• Sach-SW: Genetic Polymorphism
• Sach-SW: Pattern Recognition Receptor
• Sach-SW: Receptor Structure-Function
• Sach-SW: Toll Receptors
• Sach-SW: Toll-like Receptors (TLR)
• K10plus-PPN: 1838244875

Abstract

The innate immune system employs Toll-like receptors (TLRs) for the detection of invading microorganisms based on distinct molecular patterns. For example, TLR9 is activated by microbial DNA and also by short therapeutic CpG-containing oligonucleotides (CpG-ODN). TLR9 activation leads to the production of interferons and the priming of humoral adaptive immune responses. Unfortunately, the principles of ligand recognition by TLR9 are poorly understood, and genetic variants of TLR9, which may affect its function, have not been characterized systematically on the molecular level. We therefore sought to functionally characterize reported single nucleotide polymorphisms of TLR9 in the HEK293 model system. We discovered that two variants, P99L and M400I, are associated with altered receptor function regarding NF-κB activation and cytokine induction. Our investigations show that for the most functionally impaired variant, P99L, the ability to respond to physiological and therapeutic TLR9 ligands is severely compromised. However, CpG-ODN binding is normal. CpG-ODN recognition by TLR9 thus appears to involve two separate events, CpG-ODN binding and sensing. Our studies highlight Pro-99 as a residue important for the latter process. In genotyping studies, we confirmed that both M400I (rs41308230) and P99L (rs5743844) are relatively rare variants of TLR9. Our data add rs41308230 and rs5743844 to the list of functionally important TLR variants and warrant further research into their relevance for infectious disease susceptibility or responsiveness to CpG-ODN-based therapies.