dc.contributor.author
Fuchsberger, Felix Franz Robert
dc.date.accessioned
2021-06-08T08:39:46Z
dc.date.available
2021-06-08T08:39:46Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/30902
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-30641
dc.description.abstract
Ubiquitous glycans facilitate a plethora of important interactions namely cancer-host, host-pathogen,
host-self interactions. Interaction with theses carbohydrates is enabled by lectins and the effects of
these interactions can range from redundant to essential. Lectins are exposed on mammalian cell
surfaces where they identify the information encoded in glycans and transfer it into signal transduction
pathways. Such signal transduction pathways are complex and difficult to analyse. However,
quantitative data with single cell resolution provides means to disentangle the associated signalling
cascades. C-Type lectin receptors (CLRs) expressed on immune cells were chosen as a model system to
study their capacity to transmit information encoded in glycans of incoming particles. To this end,
monocytic cell lines cell lines expressing DC-SIGN, MCL, dectin-1, dectin-2, and mincle, as well as TNFAR
and TLR-1&2 were established. Based on the study of Cheong et al., 2011 the amount of transmitted
information was quantified by following NFκB dependent GFP expression. While most receptors did
have a channel capacity of at least 1 bit, it was found that dectin-2 has a lower capacity to transmit
information than other lectins. Especially the comparison to the related lectin mincle is interesting, since
mincle uses the same pathway effectively. Furthermore, information transmission of dectin-2 could not
be enhanced by other lectins or signalling molecules. Yet upon closer analysis it was found that the
sensitivity of the dectin-2 signal transduction pathway can be enhanced by overexpression of its co-
receptor FcRγ, but surprisingly its transmitted information cannot. Moreover, it was suggested how
potential autoimmunity might be a cause for dectin-2’s inefficient signalling. The question of signal
integration was also approached: How do cells combine the flow of information from multiple
receptors? It was shown that the signal of dectin-2 and dectin-1 are being integrated as a compromise
between both receptors. The reason for this compromise might be the activity of the phosphoprotein
SYK, present in both dectin-1 and dectin-2 signal transduction pathways.
By using the established assays and cell lines, soluble beta glucans (SBGs) were discovered to be potent
stimulators of dectin-1, where sensitivity to the SBGs was highly variable and dependent on their β-
glucan side chains. Various different ligands for mincle on the other hand resulted in a similar signalling
behaviour. Building on insight in targeted delivery to lectins, it was shown how nucleic acids can be
delivered to Langerin expressing cells and used to reprogramme the cells, a technology of tremendous
potential for vaccination strategies and (non-germline) genetic editing.
8
Taken together, the concepts of information theory with single cell resolved data enabled the
quantification of CLRs signalling behaviour and signal integration. By using dectin-2 and other lectins as
example it was demonstrated how the receptor itself determine the efficiency and therefore outcome
of the signal transduction pathways. Moreover, the potential to explore glycan lectins interactions in
drug targeting was exemplified by delivering mRNA via Langerin or demonstrating the dependency of
dectin-1 sensitivity upon the β-glucan side chains of its ligands.
en
dc.format.extent
104 Seiten
dc.rights.uri
https://creativecommons.org/licenses/by-nc/4.0/
dc.subject
glycobiology
en
dc.subject
C-type lectins
en
dc.subject.ddc
500 Natural sciences and mathematics::570 Life sciences::570 Life sciences
dc.title
Quantification of C-type lectin receptors signal transduction
dc.contributor.gender
male
dc.contributor.firstReferee
Rademacher, Christoph
dc.contributor.furtherReferee
Daumke, Oliver
dc.date.accepted
2021-05-25
dc.identifier.urn
urn:nbn:de:kobv:188-refubium-30902-3
refubium.affiliation
Biologie, Chemie, Pharmazie
dcterms.accessRights.dnb
free
dcterms.accessRights.openaire
open access