Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Vertebrates have evolved acquired immunity, but to detect an infection in its early stages they, nonetheless, rely on Toll-like receptors (TLRs) and other innate immune receptors. We have performed genomewide mutagenesis screens in an immortalized murine cell line to study nuclear factor kappaBeta (NF-kappaB) signaling in the context of innate immunity. To enable metabolic and physical selection for alterations in NF-kappaB signaling, we equipped cells with multiple reporter genes. Despite the diploid nature of the cells, multiple mutants unresponsive to lipopolysaccharide and CpG DNA were isolated from as few as 10 million mutagenized cells. Mutant clones may lead to the discovery of novel genes, and in combination with syngeneic wild-type reporter cells, they may allow a detailed functional analysis of NF-kappaB signaling. Compared with the use of whole animals in genetic screens, somatic cell genetics allows the isolation of genes required for innate immunity, even if these genes also have an essential function in development. Our discovery of an essential role for the endoplasmic reticulum chaperone gp96 (Grp94) in the maturation of TLRs and our work on the regulation of the inhibitor of nuclear factor kappaB kinase (IKK) complex by Nemo will be discussed in this context.

Original publication




Journal article


Sci Signal

Publication Date





Animals, Dinucleoside Phosphates, Genes, Reporter, I-kappa B Kinase, Immunity, Innate, Membrane Glycoproteins, Mutation, NF-kappa B, Signal Transduction, Toll-Like Receptors, Ubiquitination