HUWE1 controls tristetraprolin proteasomal degradation by regulating its phosphorylation

April 20, 2023

Tristetraprolin (TTP) is an important regulator of the innate immune system that regulates the inflammatory response. How TTP is regulated, however, is poorly understood. In their work published in eLife, the lab of Gijs Versteeg (Max Perutz Labs, and member of our Special Research Program) has gained insight into how this critical immune regulator is kept in check. Together with collaborators, among them Tim Clausen (IMP, and also member of our Special Research Program), they identified the ubiquitin E3 ligase HUWE1 as an important factor that controls the degradation of TTP.

Our innate immune system is an important part of the defense against harmful pathogens, but it is a double-edged sword. Inflammation is a systemic response that recruits specialized immune cells and signaling molecules to the site of infection. Extensive inflammation, however, can lead to local tissue damage and is a hallmark of many autoimmune diseases. To prevent excessive inflammation, cells have developed mechanisms to keep these responses in check. TTP is an RNA-binding protein that plays an important role in attenuating the inflammatory response by helping to degrade mRNAs that encode for pro-inflammatory molecules. A key but poorly understood mechanism of TTP regulation is its timely proteolytic removal: TTP is degraded by the proteasome through yet unidentified phosphorylation-controlled drivers.

In her PhD project, first author of the study Sara Scinicariello set out to understand more about how TTP is regulated, and together with the collaborators identified the ubiquitin E3 ligase HUWE1 as a previously unrecognized regulator of TTP.

Read the full story in the News from the Max Perutz Labs here.

Publication:

Sara Scinicariello, Adrian Soderholm, Markus Schäfer, Alexandra Shulkina, Irene Schwartz, Kathrin Hacker, Rebeca Gogova, Robert Kalis, Kimon Froussios, Valentina Budroni, Annika Bestehorn, Tim Clausen, Pavel Kovarik, Johannes Zuber, Gijs A Versteeg:

HUWE1 controls tristetraprolin proteasomal degradation by regulating its phosphorylation.

eLife.2023 Mar 24

https://doi.org/10.7554/eLife.83159