The integrin alpha-V-beta-5 heterodimer and its application in the study of toll-like receptor signaling and expression

Abstract

<P>TOLL-LIKE RECEPTORS (TLRS) ARE INVOLVED IN INNATE IMMUNE RESPONSES TO MICROBIAL PRODUCTS. IT IS NOT KNOWN WHETHER DIMERIZATION IS AN ACTIVATION MECHANISM FOR ALL TLRS. THE SUBCELLULAR SITES FOR TLR LIGAND RECOGNITION AND THE SIGNALS IN TLRS THAT MEDIATE ITS TARGETING AND ACTIVATION ARE ALSO UNCLEAR. THESE QUESTIONS WERE INVESTIGATED USING CHIMERIC CONSTRUCTS OF TLRS AND ALPHAVBETA5 INTEGRIN. CO-EXPRESSION OF ALPHAV-TLR AND BETA5-TLR CHIMERAS GENERATED ALPHAVBETA5-MEDIATED TLR HOMODIMERS OR HETERODIMERS WHICH WERE EXAMINED FOR THEIR INDUCTION OF NF-KB ACTIVATION. ONLY TLR4/4 HOMODIMER AND TLR2/1, TLR2/6 HETERODIMERS WERE ABLE TO ACTIVATE NF-KB. STUDIES USING MONOMERIC CHIMERAS OF SINGLY TRANSFECTED BETA5-TLRS, TOGETHER WITH FULL-LENGTH TLRS, SHOWED THAT TLR3, TLR5, TLR7 AND TLR9 HAVE PREDOMINANT INTRACELLULAR LOCALIZATION IN CD71-POSITIVE EARLY ENDOSOMES AND/OR THE GOLGI. THIS LOCALIZATION WAS DEPENDENT ON BOTH THE ECTODOMAIN AND CYTOPLASMIC DOMAIN OF TLRS. NOVEL MUTATIONS AFFECTING