Current Research
Aims
Our lab is interested to understand the molecular function of the mammalian NLR proteins and their contribution to innate and adaptive immune responses.
There is good evidence that these proteins make essential contributions to immune responses and inflammatory reactions general. This is witnessed by polymorphisms in several NLR genes that are associated with severe inflammatory disorders in human, such as Blau-Syndrom, Crohn’s disease and CAPS.
Deciphering the functions of the members of these interesting protein family is therefore suited to devise new therapeutic approaches for such disease in the long run.
Our current research focuses on the following topics.
The role of F-actin in NLR-mediated signal transduction
NOD1 is an intracellular pathogen recognition receptor that contributes to anti-bacterial innate immune responses, adaptive immunity and tissue homeostasis. NOD1-induced signalling relies on actin remodeling, however, the details of the connection of NOD1 and the actin cytoskeleton remained elusive.
We showed that in human epithelial cells, Nod1 is localized in the cytosol and at F-actin rich regions at the plasma membrane. This membrane association is dependent on the integrity of the protein, on its signalling capacity and on an intact actin cytoskeleton (see Kufer et al. CellMicro 2008 and Zurek et al. Innate Immunity 2012).
Using a druggable-genome wide siRNA screen, we recently identified the cofilin phosphatase SSH1 as a specific and essential component of the NOD1 pathway (see Bielieg and Lautz et al. PLOSPathogens 2014).
In ongoing work, we aim to elucidate the details of how the actin skeleton is linked to NOD1 and NOD2-mediated immune responses.
Many pathogenic bacteria induce profound changes in the host cell aktin cytoskeleton. Our results suggest that NOD1 is involved in a pathway that induces inflammatory reactions in response to such perturbations.
For details see our recent review article on this topic.
„Guardians of the Cell: Effector-Triggered Immunity Steers Mammalian Immune Defense”
(Kufer et al. Trends in Immunology 2019)
Novel roles of the NOD1/2-associated kinase RIPK2 – formation of RIPosomen
We are also interested in the function of the kinase RIPK2, which is essential for signal transduction of NOD1/2. RIPK2 is regulated by complex post-translational modifications (PTM). We were recently able to show that after activation of NOD1 or NOD2, RIPK2 forms specific complexes in the cytosol of the cell, which are regulated by PTM (Ellwanger et al. Life Sci Alliance. 2019). We refer to these complexes as "RIPosomes". In current projects, we are analyzing the interaction of RIPK2 and its dynamics during bacterial infections.
Transcriptional regulation of MHC class I gene expression
Although most NLR proteins act in cell autonomous immune pathways, some do not function as classical pattern-recognition receptors. One such NLR protein is the MHC class II transactivator (CIITA), which is essential for the expression MHC class II genes. We and others found that human NLRC5 shuttles to the nucleus and mediates the transcriptional activates of MHC class I genes in a manner similar to CIITA (see Neerincx et al. JI 2012).
On the other hand, we have evidence that NLRC5 also has functions independent of its role in MHC gene regulation and contributes to type I interferon responses (see Neerincx et al. Front Immunol. 2013).
Ongoing research projects aim to understand the molecular details and the proteins involved in NLRC5-mediated MHC I gene transcription and the contribution of NLRC5 to innate and adaptive immune responses (see Benko et al, Front Immunol. 2017).
Antigen presentation via MHC molecules is essential for the activation of T cells and thus for any adaptive immune response. MHC class I molecules are thereby critically involved anti-viral and anti-tumor responses mediated by cytotoxic T lymphocytes. Our studies aim to decipher the underlying mechanism and to identify new targets for therapeutic intervention.
Analysis of the function of "orphan" human and murine NLR proteins
Many of the human and murine NLR-family members are still poorly described. We aim to address their role in human cells and to unravel their physiological role using novel mouse models.
One example is NLRP10, for which we identified a novel role in NOD1-medited immune responses towards bacterial infection (see Lautz et al. CellMicro 2012, Mirza et al. JI 2019).
Current work is also investigating the role of NLR proteins in the antiviral interferon response. Here we were recently able to identify a new function of NLRP11 in this process (Ellwanger et al. JBC 2018).
For more details on NLR biology, please visit current review article, available at the
Wiley Online Library
Functions of NLR proteins in obesity
Some members of the NLR family contribute to the processes that are involved in the development of obesity (see our review article in Aktuelle Ernährungsmedizin). In ongoing work, we are investigating the function of selected NLR protein in obesity using mouse models and cell culture attempts.
