Abstract
AbstractThe tumor necrosis factor receptor-associated factor 6 (TRAF6) is a central molecule in multiple signaling pathways, i.e. the TNF receptor, the Toll-like receptors (TLRs), and interleukin-1 receptor (IL-1R) pathways. Upon pathogen associated molecular patterns (PAMPs) or damage associated molecular patterns (DAMPs) stimulations, TRAF6 activates downstream of NF-κB signaling. However, the precise mechanism of how TRAF6 activates downstream molecules remains unclear.Here, we demonstrate that TRAF6 acts as a sensor for upstream signals to initiate liquid-liquid phase separation (LLPS) of itself and downstream proteins, forming membraneless condensates. Subsequent recruitment, enrichment and activation of downstream effectors in the condensates lead to robust inflammatory signal transduction. The multivalent interactions mediated by its RING domain, zinc finger domain 1, and coiled-coil domain mediates the LLPS process. Forced phase separation of TRAF6 induced NF-κB activation. Disruption of TRAF6 phase separation abrogates activation of NF-κB signaling. Overall, we uncover the spatial organization of molecules by TRAF6 through phase separation as a subcellular platform to activate inflammatory signaling. Targeting TRAF6 phase separation hold promises for therapeutics aiming autoimmune diseases, inflammation and cancers.
Publisher
Cold Spring Harbor Laboratory
Cited by
3 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献