Nanoscale arrangement of apoptotic ligands reveals a demand for a minimal lateral distance for efficient death receptor activation

Julia Ranzinger, Anja Krippner-Heidenreich, Tamas Haraszti, Eva Bock, Jessica Tepperink, Joachim P. Spatz, Peter Scheurich

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

38 Citaten (Scopus)

Samenvatting

Cellular apoptosis, the prototype of programmed cell death, can be induced by activation of so-called death receptors. Interestingly, soluble and membrane-bound members of death receptor ligands can differentially activate their receptors. Using the death receptor ligand tumor necrosis factor (TNF) presented on a surface in a nanoscaled pattern with spacings between 58 and 290 nm, we investigated its requirements for spatial arrangement and motility to efficiently activate TNF receptor (TNFR)1 and TNFR2 as well as its chimeras TNFR1-Fas and TNFR2-Fas. We show that the mere mechanical fixation of TNF is insufficient to efficiently activate TNFR2 that is responsive to only the membrane bound form of TNF but not its soluble form. Rather, an additional stabilization of TNFR2(-Fas) by cluster formation seems to be mandatory for efficient activation. In contrast, TNFR1(-Fas) is strongly activated by TNF spaced within up to 200 nm distances, whereas larger spacings of 290 nm fails completely. Furthermore, unlike for TNFR2(-Fas) no dose-response relationship to increasing distances of nanostructured ligands could be observed for TNFR1-(Fas), suggesting that compartmentalization of the cell membrane in confinement zones of approximately 200 nm regulates TNFR1 activation.

Originele taal-2Engels
Pagina's (van-tot)4240-4245
Aantal pagina's6
TijdschriftNano Letters
Volume9
Nummer van het tijdschrift12
DOI's
StatusGepubliceerd - 9 dec. 2009
Extern gepubliceerdJa

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