Effekte chemisch induzierter β-Arrestin-1-Translokation an die Chemokinrezeptoren CXCR4 und CCR5

Vogt, Viola

dc.contributor.advisor	Oppermann, Martin Prof. Dr.
dc.contributor.author	Vogt, Viola
dc.date.accessioned	2021-07-19T10:38:44Z
dc.date.available	2021-08-03T00:50:04Z
dc.date.issued	2021-07-19
dc.identifier.uri	http://hdl.handle.net/21.11130/00-1735-0000-0008-58B0-E
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-8739
dc.language.iso	deu	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc	610	de
dc.title	Effekte chemisch induzierter β-Arrestin-1-Translokation an die Chemokinrezeptoren CXCR4 und CCR5	de
dc.type	doctoralThesis	de
dc.title.translated	Effects of chemically induced β-arrestin 1 translocation to chemokine receptors CXCR4 and CCR5	de
dc.contributor.referee	Oppermann, Martin Prof. Dr.
dc.date.examination	2021-07-27
dc.description.abstracteng	Based on heterodimerization of chemokine receptors CXCR4 and CCR5 with β-arrestin 1 in co-expressing HEK 293 cells, this study shows β-arrestin 1-dependent effects without usual ligand induced receptor and G protein activation. These effects were compared to those of a constitutively active β arrestin 1R169E mutant. In result, ligand-independent effects of chemically induced β-arrestin 1 translocation to unstimulated chemokine receptors were found: β-arrestin 1 desensitizes, internalizes and triggers MAPK signaling without G protein activation. Regarding receptor internalization, the β-arrestin-1R169E mutant exceeds wildtype β-arrestin 1 effects. β-arrestin 1 conformation changes seem to have a relevant impact on cellular process regulation. First, HEK 293 cells co-expressing CXCR4 / CCR5 with β-arrestin 1 / β-arrestin 1R169E combined with c-terminally added dimerization domains from a heterodimerization system were established. Due to chemically induced contact between chemokine receptor and interacting β-arrestin 1, receptor desensitization occurred. Ligand-independent β-arrestin 1 translocation to CCR5 via heterodimerization reached a similar receptor internalization level compared with usual ligand stimulation. CXCR4 internalization after chemically induced β-arrestin 1 translocation reached a comparable level but did not attain its chemokine induced internalization maximum. Regarding intracellular receptor trafficking, no receptor distribution differences were found between ligand stimulation and chemically induced β-arrestin 1 translocation. Moreover, β-arrestin 1 co-accumulated with both chemokine receptors in intracellular departments via chemically induced translocation. This co-accumulation did not occur in ligand stimulated cells with β-arrestin 1 wildtype but increased after ligand stimulation in cells with β-arrestin 1R169E mutants. In addition, β-arrestin 1R169E had a stronger receptor internalization potential compared to the wildtype. Chemically induced β-arrestin 1 translocation to the chemokine receptors CXCR4 and CCR5 showed ligand-independent ERK1/2 activation, whereas β-arrestin 1R169E mutants did not have stronger effects on ERK1/2 activation compared with wildtype β-arrestin 1.	de
dc.contributor.coReferee	Schu, Peter Prof. Dr.
dc.subject.ger	β-Arrestin-1	de
dc.subject.ger	β-Arrestin-1R169E	de
dc.subject.ger	CXCR4	de
dc.subject.ger	CCR5	de
dc.subject.ger	Heterodimerisierung	de
dc.subject.ger	Rezeptordesensibilisierung	de
dc.subject.ger	Rezeptorinternalisierung	de
dc.subject.ger	ERK1/2	de
dc.subject.ger	β-Arrestin-abhängig	de
dc.subject.eng	β-arrestin 1	de
dc.subject.eng	β-arrestin 1R169E	de
dc.subject.eng	CXCR4	de
dc.subject.eng	CCR5	de
dc.subject.eng	heterodimerization	de
dc.subject.eng	receptor desensitization	de
dc.subject.eng	receptor internalization	de
dc.subject.eng	ERK1/2	de
dc.subject.eng	β-arrestin-dependent	de
dc.identifier.urn	urn:nbn:de:gbv:7-21.11130/00-1735-0000-0008-58B0-E-1
dc.affiliation.institute	Medizinische Fakultät	de
dc.subject.gokfull	Medizin (PPN619874732)	de
dc.subject.gokfull	Immunologie / Allergologie / Umweltmedizin / Medizinische Ökologie - Allgemein- und Gesamtdarstellungen (PPN619875445)	de
dc.subject.gokfull	Biologie (PPN619875151)	de
dc.subject.gokfull	Biochemie / Physiologische Chemie / Pathobiochemie - Allgemein- und Gesamtdarstellungen (PPN619875313)	de
dc.description.embargoed	2021-08-03
dc.identifier.ppn	1763699196

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