Nuclear licensing of cytoplasmic mRNA decay in inflammation

Our immune system is constantly exposed to insults originating from outside, such as pathogens, or from within, such as dysfunctional cells. To eliminate these threats, the immune system launches an inflammatory response, which must be precisely regulated to avoid excessive, tissue-damaging inflammation. The healthy balance between pro-inflammatory and anti-inflammatory reactions is referred to as immune homeostasis. The proposed project will investigate how immune homeostasis is maintained, focusing on the mechanisms that efficiently terminate inflammation. This process is highly dependent on the anti-inflammatory protein TTP, which acts as an extraordinary efficient yet sensitive brake that halts inflammation only after the insult has been successfully removedbut not earlier. TTP controls inflammation by promoting the degradation of messenger RNA molecules that encode pro-inflammatory proteins, such as cytokines. It remains unclear how TTP selects its RNA targets so that they are degraded neither too early nor too late. Premature cytokine RNA degradation would lead to an insufficient immune response, whereas delayed degradation would cause uncontrolled inflammationboth detrimental outcomes. Previous studies from the project leaders laboratory revealed that TTP facilitates the timely degradation of selected RNAs by binding to them at the appropriate phase of the inflammatory responseensuring that the immune systems brake is applied precisely when needed. The proposed project will clarify how the timing of TTP binding to RNA is regulated. Initial experiments suggest that, surprisingly, TTP binds its target RNAs already during their synthesisthat is, during transcription. This unexpected mechanism ensures that selected RNAs are marked for degradation early in their lifespan, before they serve as templates for the production of pro-inflammatory proteins such as cytokines. Most importantly, this mechanism may explain the exceptionally high efficiency of TTP in preventing hyperinflammation. The anticipated results of the project will shed light on how RNA degradation by TTP maintains immune homeostasis and supports healthy immune responses.