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Somatic cell genetics for the study of Toll like receptors and NF-kB

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Somatic cell genetics for the study of Toll like receptors and NF-kB

Vertebrates have evolved adaptive immunity but to detect infection they still rely on Toll-like and other innate immune receptors. To gain further insight into TLR signalling and NF-kB activation, we have set up a program in somatic cell genetics and have isolated mutant cells based on their unresponsiveness to TLR agonists. So far we have identified one novel gene, gp96, which we show is specifically required for the maturation of multiple TLRs in the endoplasmic reticulum. We have also obtained clones deficient in Tlr9, Unc93b1, Myd88, Irak1, IKKbeta, RelA and Nemo. I will discuss the value of gene deficient reporter cells for mechanistic studies of gene function using Nemo as an example. Our collection of Nemo mutants comprises mainly signalling deficient clones but it also contains a gain of function allele that activates NF-kB constitutively. We initially found that in contrast to wild type Nemo signalling deficient alleles did neither bind ubiquitin nor were they ubiquitylated. By introducing the activating mutation into signalling impaired alleles we restored their ubiquitylation and created mutants constitutively activating NF-B without repairing their ubiquitin binding defect. This demonstrates that constitutive activity arises downstream of ubiquitin binding but upstream of ubiquitylation. Such constitutive activity reveals a signal processing function for Nemo beyond that of a mere ubiquitin binding adaptor. We propose that this signal processing involves homophilic CoZi interactions as suggested by the enhanced affinity of CoZi domains from constitutively active Nemo.

This talk is part of the Departmental Seminar Programme, Department of Veterinary Medicine series.

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