Project

The study of RIPK1 phosphorylation in TNF-mediated infection and disease

Duration
01 October 2017 → 30 September 2020
Funding
Research Foundation - Flanders (FWO)
Research disciplines
No data available
Keywords
RIPK1
 
Project description

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.