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SUMMARY:Somatic cell genetics for the study of Toll like receptors and NF-
 kB - Dr Felix Randow\, MRC Laboratory of Molecular Biology\, Cambridge
DTSTART:20080130T163000Z
DTEND:20080130T173000Z
UID:TALK9266@talks.cam.ac.uk
CONTACT:5684
DESCRIPTION:Somatic cell genetics for the study of Toll like receptors and
  NF-kB\n\nVertebrates have evolved adaptive immunity but to detect infecti
 on 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 o
 n their unresponsiveness to TLR agonists. So far we have identified one no
 vel gene\, gp96\, which we show is specifically required for the maturatio
 n of multiple TLRs in the endoplasmic reticulum. We have also obtained clo
 nes 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 initial
 ly found that in contrast to wild type Nemo signalling deficient alleles d
 id neither bind ubiquitin nor were they ubiquitylated. By introducing the 
 activating mutation into signalling impaired alleles we restored their ubi
 quitylation and created mutants constitutively activating NF-B without 
 repairing their ubiquitin binding defect. This demonstrates that constitut
 ive activity arises downstream of ubiquitin binding but upstream of ubiqui
 tylation. 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.\
 n
LOCATION:Lecture Theatre 1\, Department of Veterinary Medicine
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