Lin Liu - Inflammation division

Lin Liu - Inflammation division

Start Time: 
Wed, 27/05/2020 - 1:00pm
End Time: 
Wed, 27/05/2020 - 2:00pm

More red tape: an ancient post translational modification is a new regulator of TNFR1 induced death

Online seminar: access Slido and enter code #WEHIWEDNESDAY
Including Q&A session

​Wednesday seminar hosted by Professor John Silke (this is a PhD confirmation seminar)

Tumor necrosis factor (TNF) is a master inflammatory cytokine that can, depending on the circumstances, promote survival and proliferation or induce cell death. Anti-TNF drugs have proven strikingly successful in treating inflammatory diseases such as rheumatoid arthritis, psoriasis and IBD but it is still unclear exactly why. For a long time it was thought that they work solely by preventing TNF induced transcription of other inflammatory cytokines, but more recently it has been proposed that one of their major anti-inflammatory functions is to prevent TNF induced death.

Given its potent activity it is unsurprising that TNF signalling is heavily regulated by a plethora of post-translational modifications, including phosphorylation and diverse types of ubiquitin chains. However, most studies have focused on the membrane bound, transcription activating, complex (complex-1), and the composition and modifications in the cytosolic, caspase containing, death inducing complex (complex-2) remain far less well defined.

To identify and characterize novel interactors and modifications in complex-2, Lin generated 3xFLAG-tagged caspase-8 knock-in mice. Using a mass spectrometry approach and primary cells from these knock-in mice, she found that the enzyme tankyrase is recruited to complex-2. Tankyrases are ADP ribose polymerases, and belong to an ancient group of enzymes, that post-translationally modify proteins with ADP-ribose. Lin found that during TNF signalling, complex-2 becomes poly (ADP-ribosyl)ated (PARsylated) in a tankyrase dependent manner. Furthermore, tankyrase-specific inhibitors sensitize cells to TNF-induced cell death, which correlates with increased levels of complex-2. This suggests that normally tankyrase helps limit TNF induced death. Mechanistically, tankyrase may modulate the stability of complex-2 by recruiting RNF146, an E3 ubiquitin ligase, that in turn promotes ubiquitylation of complex-2. This newly discovered checkpoint dramatically expands our understanding of how TNF induced death is regulated and given the availability of tankyrase drugs may have clinical applications.