|Titel:||Role of the Actin Depolymerizing Factors ADF and Cofilin in Murine Macrophages (Mus musculus; Linnaeus, 1758)||Sonstige Titel:||Rolle der Aktin depolymerisierenden Proteine ADF und Cofilin in murinen Makrophagen (Mus musculus; Linnaeus, 1758)||Sprache:||Englisch||Autor*in:||Jönsson, Friederike||Schlagwörter:||ADF; Macrophage; Cytoskeleton; Cofilin; Actin||GND-Schlagwörter:||Cofilin; Actin; Makrophage; Zellskelett; Phagozytose; Morphologie; Antigenpräsentation; Zellmigration; Ligand <Biochemie>; Proliferation||Erscheinungsdatum:||2007||Tag der mündlichen Prüfung:||2007-02-16||Zusammenfassung:||
The actin cytoskeleton is a structure found in all eukaryotes, known to be essential for a wide range of cellular processes. The remodelling of the actin cytoskeleton is regulated by a large number of proteins, commonly known as actin binding proteins.
Recently the actin cytoskeleton as a central component of cellular architecture has gained attention as a regulator of immune functions. One goal of this thesis was to shed some light on the regulation of the actin cytoskeleton in murine macrophages, by investigating the function of the two actin depolymerizing factors ADF and cofilin. ADF and cofilin are highly conserved molecules that enhance actin filament turnover by severing and depolymerization of filaments.
Using a genetic approach, I studied the loss-of-function of ADF and cofilin in murine macrophages. My work demonstrated that cofilin is essential for macrophage polarization, migration, and cytokinesis. Lack of cofilin resulted in a decreased ability to re-organize the actin cytoskeleton as indicated by the accumulation of cortical F-actin and the alterations in cell morphology. Interestingly, other actin dependent processes like phagocytosis or cell attachment were not disturbed in cofilin null macrophages. In terms of immunological functions, I could demonstrate that cofilin is required for antigen presentation by macrophages, suggesting an important role of cofilin in the formation of the immunological synapse.
One unexpected, finding described in my thesis is that the cofilin homolog ADF has a distinct role in vivo. Macrophages lacking ADF showed no functional defects and were similar to wild type cells in all the experiments performed.
In order to better characterize the common and distinct activities of cofilin and ADF, I developed two different strategies. First, I generated a conditional allele in the mouse which will allow tissue specific exchange of the cofilin expression by ADF.
Second, using a proteomics approach, I was able to identify novel binding partners for cofilin and ADF. These protein ligands characterized from ADF/cofilin complexes suggested a not yet recognized role of the two proteins also in the nucleus. There ADF and cofilin might regulate actin in controlling chromatin structure, transcription, and mRNA processing.
In conclusion, ADF and cofilin play distinct roles in macrophages in the regulation of immune cell functions, suggesting that both proteins are working in independent pathways to control actin turnover. The potential differences in regulation and the selective interaction of cofilin/ADF with partners other than actin will be an interesting and important aspect of future work. A better understanding of ADF and cofilin function and regulation might eventually allow to modify or interfere with immune cell responses under pathological conditions.
|URL:||https://ediss.sub.uni-hamburg.de/handle/ediss/1705||URN:||urn:nbn:de:gbv:18-32749||Dokumenttyp:||Dissertation||Betreuer*in:||Fleischer, Bernhard (Prof. Dr.)|
|Enthalten in den Sammlungen:||Elektronische Dissertationen und Habilitationen|
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