TRAF2 binds to TIFA via a novel motif and contributes to its autophagic degradation.

A signal transduction pathway has been defined in which ADP-heptose activates the mammalian protein kinase ALPK1, which phosphorylates the adaptor protein TIFA, inducing its polymerisation and interaction with the E3 ubiquitin ligases TRAF2/c-IAP1 and TRAF6. These E3 ligases drive activation of the transcription factors NF-κB and AP-1, culminating in the production and secretion of inflammatory mediators to combat microbial infection. TRAF6 is essential in this process, but how TRAF2 interacts with TIFA and its role in the pathway is unclear. Here, we identify two conserved sequence motifs in TIFA essential for TRAF2 interaction, one of which (Pro159-Xaa-Xaa-Glu162) is novel. We additionally report that ADP-heptose induces TIFA degradation by autophagy and that both TRAF2 and TRAF6 contribute to this process. These findings advance understanding of how TRAF2 regulates the ALPK1-TIFA signalling pathway.