SPATA2: more than a missing link

The assembly of the TNFR1 signalling complex (TNF-RSC) depends on K63- and M1-linked ubiquitylation, promoting the recruitment of complex constituents and the stability of the complex. Ubiquitylation is a dynamic process, controlled by E3 ubiquitin ligases as well as deubiquitinases, such as CYLD and OTULIN. A novel molecule, SPATA2, which is crucial for recruiting and activating the deubiquitinase CYLD within the TNF-RSC, has now been identified by four different studies. Loss of SPATA2 was shown to result in increased TNF-, but also NOD2-mediated proinflammatory signalling. Importantly, SPATA2 is instrumental for TNF-induced cell death, and a closer look at these findings suggests that SPATA2 possibly has functions beyond promoting the activity of CYLD.