Dr. Zong-Ping Xia’s group published a research article entitled “Oligomerization-primed coiled-coil domain interaction with Ubc13 confers processivity to TRAF6 ubiquitin ligase activity” on Nature Communications on October 9, 2017.
The NF-κB signaling pathway is important for immune, inflammatory and stress response of cells. Dysregulation of NF-κB activity is linked to inflammatory disorders, autoimmune and neurodegenerative disease, as well as cancer. The range of NF-κB-inducing stimuli further extends to physical,chemical and physiologicalstresses. The ubiquitin ligase TRAF6, together with ubiquitin-conjugating enzyme Ubc13/Uev1, catalyzes processive assembly of unanchored K63-linked polyubiquitin chains essential for TAK1 activation in the IL-1R/TLR pathways. However, what feature of the polyubiquitin chains that contributes to TAK1 activation is unknown. What domain and how it functions to enable TRAF6’s processivity are largely uncharacterized.
In this study, Dr.Xia’s group found that only long polyubiquitin chains are potent in TAK1 activation. This preference of long polyubiquitin chains determines TRAF6 to be a processive enzyme. In addition, they revealed that TRAF6 coiled-coil (CC) domain is crucial to enable its E3 ligase processivity. The CC domain mediates TRAF6 higher order oligomerization, which effectively enables its RING domains to bind simultaneously to multiple Ubc13/Ub~Ubc13, therefore contributing to its processivity. Mutating or deleting the CC domain impairs TRAF6 oligomerization and processive polyubiquitin chain assembly. Fusion of the CC domain to the E3 CHIP, which is a U-box E3 ligase, renders the latter being capable of NF-κB activation. More importantly, the CC domain, after oligomerization, interacts with Ubc13/Ub~Ubc13, which renders spent Ubc13 to be recharged with Ub without its dissociation from TRAF6 to optimize TRAF6 processivity. Point mutations within the CC domain that weaken TRAF6 affinity to Ubc13/Ub~Ubc13 diminish TRAF6 processivity, which results in inactive TRAF6 in IL-1β-induced TAK1 activation. In conclusion, the results reveal that the CC oligomerization primes its interaction with Ubc13/Ub~Ubc13 to optimize the processivity of TRAF6 ubiquitin ligase activity in the IL1R/TLR signaling pathways.
Model depicting the synthesis of long free polyub chains by TRAF6.
Link:https://www.nature.com/articles/s41467-017-01290-0
