ZJU Scientists Identify Mechanism for Ubiquitin Ligase TRAF6

2017-10-12

    Transcription factors NF-κB play a crucial role in immunity and inflammation and are intimately akin to cancer, immunity-related diseases and neurodegenerative diseases. Ubiquitin ligase TRAF6, together with ubiquitin-conjugating enzyme Ubc13/Uev1, catalyzes processive assembly of unanchored K63-linked polyubiquitin chains for TAK1 activation in the IL-1R/TLR pathways. However, what domain and how it functions to enable TRAF6’s processivity are largely uncharacterized.

    The research team led by Prof. Xia Zongping, the Life Sciences Institute and the Innovation Center for Cell Signaling Network at Zhejiang University, finds that TRAF6 coiled-coil (CC) domain is crucial to enable its processivity. The CC domain mediates TRAF6 oligomerization to ensure efficient long polyubiquitin chain assembly. Mutating or deleting the CC domain impairs TRAF6 oligomerization and processive polyubiquitin chain assembly. Fusion of the CC domain to the E3 ubiquitin ligase CHIP/STUB1 renders the latter capable of NF-κB activation. Moreover, the CC domain, after oligomerization, interacts with Ubc13/Ub~Ubc13, which further contributes to TRAF6 processivity. Point mutations within the CC domain that weaken TRAF6 interaction with Ubc13/Ub~Ubc13 diminish TRAF6 processivity. Their results reveal that the CC oligomerization primes its interaction with Ubc13/Ub~Ubc13 to confer processivity to TRAF6 ubiquitin ligase activity.

Their findings are published in Nature Communications(https://www.nature.com/articles/s41467-017-01290-0).