B03: Maurer

Cell death and inflammation are often controlled by related signalling pathways. Thus, the signals inducing pro-inflammatory gene expression can under certain circumstances induce cell death by apoptosis, pyroptosis or necroptosis. Posttranslational modifications such as phosphorylation or ubiquitylation of signalling proteins in innate immune receptor complexes play an important role for the switch between cell death and survival. We have previously identified the protein SPATA2 as an important constituent of the TNFR1-signaling complex (TNFR1-SC), and could show that SPATA2 mediates the recruitment of the deubiquitinase CYLD, along with LUBAC, to the TNFR1-SC. More recently, we could demonstrate that, by its interaction with HOIP, SPATA2 -independently of CYLD- controls the deubiquitylation of LUBAC via OTULIN, and thereby LUBAC activity and receptor complex ubiquitylation. By analysis of cells deficient for Cyld, Spata2, or both genes, we found that SPATA2 promotes TNF-induced apoptosis, and this SPATA2 function is, at least in part, independent of CYLD. Here, we want to clarify the role of SPATA2 for the formation of complex II and pro-apoptotic caspase-8 activation. We will further explore potential roles of SPATA2 for inflammasome activation. Lastly, we want to elucidate the tissue specific cell death regulation by SPATA2 in vivo.