Inflammation is the initial response of the immune system to invading microbes or tissue damage.
Inflammation aims to remove cause of infection/damage and initiate the healing process.
However, uncontrolled inflammation can be self-destructive and underlies several pathologies.
Recently, it was proposed that deregulated TNF-mediated RIPK1-dependent cell death contributes
to inflammation by disrupting epithelial barriers and/or by releasing danger signals into the
extracellular environment. The functional relevance of the RIPK1-dependent pathway during
infection and in disease is currently unknown. We found that IKK IKK and MK2 directly
phosphorylate RIPK1 to keep RIPK1 in a prosurvival state after TNF stimulation. Deficiency in RIPK1
phosphorylation transforms RIPK1 into a prodeath molecule allowing it to induce cell death. This
project aims to understand how IKK- and MK2-mediated phosphorylation represses the RIPK1
prodeath function. To achieve this goal, we will perform mass spectrometry to identify the IKKand
MK2-mediated phosphorylation sites on RIPK1. Biochemical and cellular assays with RIPK1
phosphomutants will then be done to investigate at which stage in the signaling pathway(s)
phosphorylation interferes with the RIPK1 prodeath function. Finally, we will generate tools
(phosphospecific antibodies and phosphomutant knockin mice) to study the physiological
relevance of the IKK- and MK2-mediated phosphoregulation of RIPK1 in vivo.