Characterizing the in vivo importance of OTULIN in liver through mouse gene targeting studies

Inflammatory signaling pathways need to be tightly regulated in order to avoid chronic inflammation and the development of inflammatory pathology. One of the proteins responsible for such control is the enzyme OTULIN. OTULIN is a deubiquitinating enzyme which specifically cleaves linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC). LUBAC mediated linear ubiquitination is essential for NF-kB signaling in response to various stimuli, but has also been shown to protect cells from TNF-induced apoptosis. OTULIN critically controls these processes. Mice with a loss-of-function mutation in OTULIN are embryonically lethal impeding the in vivo study of OTULIN in the adult and in specific disease pathologies. The host lab has generated mice with a conditional OTULIN knockout allele allowing tissue specific OTULIN deletion. These mice will be an essential tool to identify the physiological importance of OTULIN in tissue homeostasis and inflammatory pathology. Focus of our project will be the study of OTULIN in liver physiology and pathology and the characterization of the molecular mechanisms by which OTULIN regulates NF-kB signaling and cell death responses .