Katrin Rittinger

Molecular Structure of Cell Signalling Laboratory

The innate immune response constitutes the first line of defence against invading micro-organisms. Pathogen recognition is mediated by specific pattern recognition receptors (PRRs) that activate diverse signalling pathways and initiate a pro-inflammatory response. These signalling events need to be tightly controlled as misregulation can lead to chronic inflammation and auto-immune disease. Innate immune responses can also trigger adaptive immunity and the two systems are linked through complex signalling networks.

Ubiquitination is a post-translational modification that regulates a large variety of cellular processes including signalling networks that mediate immune and inflammatory responses. The functional outcome of the modification depends on the type of ubiquitin signal generated and proteins can become modified with individual ubiquitin molecules or with polyubiquitin chains that are formed by conjugation of ubiquitin molecules via one of their seven lysine residues or the N-terminal methionine. Modification of proteins with ubiquitin depends on the sequential activity of three enzymes, the last of which are E3 ubiquitin ligases that select the substrate to be modified and in some cases also determine the type of polyubiquitin chain that will be synthesised.

Our research is focused on the characterisation of the mechanism of two different families of E3 ubiquitin ligases, the RBR (RING-Between-RING) family and the TRIM (tripartite motif) family using a combination of structural, biochemical and biophysical approaches. Members of both of these E3 families have been shown to play important regulatory roles in immune and inflammatory signalling and defects in their activity have been linked to a number of diseases.

In parallel, we are investigating how members of the NLR (NOD-like receptor) family of intracellular pattern recognition receptors respond to the presence of bacteria and danger signals and trigger cytokine production and the activation of MAP kinases and the transcription factor NF-╬║B. We are particularly interested in those NLR-activated signalling pathways that are regulated by ubiquitination.

Figure 1

UBAC is a multi-subunit RBR ligase that synthesizes linear ubiquitin chains with high specificity. The structure of the active HOIP-ubiquitin transfer complex shown here explains how the LUBAC subunit HOIP recognises the donor and acceptor ubiquitin and determines chain linkage specificity. (Click to view larger image)

Selected publications

Stieglitz, B., Rana, R.R., Koliopoulos, M.G., Morris-Davies, A.C., Schaeffer, V., Christodoulou, E., Howell, S., Brown, N.R., Dikic, I., and Rittinger, K. (2013). Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP. Nature 503, 422-426.

Stieglitz, B., Haire, L.F., Dikic, I., and Rittinger, K. (2012). Structural Analysis of SHARPIN, a Subunit of a Large Multi-protein E3 Ubiquitin Ligase, Reveals a Novel Dimerization Function for the Pleckstrin Homology Superfold. J Biol Chem 287, 20823-20829.

Stieglitz, B., Morris-Davies, A.C., Koliopoulos, M.G., Christodoulou, E., and Rittinger, K. (2012). LUBAC synthesizes linear ubiquitin chains via a thioester intermediate. EMBO Rep 13, 840-846.

Fridh, V., and Rittinger, K. (2012). The Tandem CARDs of NOD2: Intramolecular Interactions and Recognition of RIP2. PLoS One 7, e34375.

Katrin Rittinger

+44 (0)20 379 62274

  • Qualifications and history
  • 1994 PhD in Chemistry, University of Heidelberg and Max-Planck Institute (MPI) for Medical Research, Germany
  • 1995 Postdoctoral Fellow at MPI for Molecular Physiology, Dortmund, Germany
  • 1996 Postdoctoral Fellow at MRC-NIMR, London, UK (EMBO Long-term and Marie-Curie Fellow)
  • 2000 Group Leader, Medical Research Council National Institute for Medical Research, London, UK
  • 2015 Group Leader, the Francis Crick Institute, London, UK