Toll-like receptor 4 (Tlr) interactor with leucine-rich repeats (Tril) functions as a Tlr co-receptor to mediate innate immunity in adults. In Xenopus embryos, Tril triggers degradation of the Transforming Growth Factor ß (Tgfß) family inhibitor, Smad7. This enhances Bone morphogenetic protein (Bmp) signaling to enable ventral mesoderm to commit to a blood fate. Here we show that Tril simultaneously dampens Nodal signaling by catalytically activating the ubiquitin ligase Nedd4l. Nedd4l then targets Nodal receptors for degradation. How Tril signals are transduced in a non-immune context is unknown. We identify the ubiquitin ligase Pellino2 as a protein that binds to the cytoplasmic tail of Tril, and subsequently forms a complex with Nedd4l and another E3 ligase, Traf6. Pellino2 and Traf6 are essential for catalytic activation of Nedd4l, both in Xenopus and in mammalian cells. Traf6 ubiquitinates Nedd4l, which is then recruited to membrane compartments where activation occurs. Collectively, our findings reveal that Tril initiates a non-canonical Tlr-like signaling cascade to activate Nedd4l, thereby coordinately regulating the Bmp and Nodal arms of the Tgfß superfamily during vertebrate development.
Support or Funding Information
This work was supported by the National Institutes of Health (RO1HD067473-06 to JLC, and T32DK007115 to YSG).
Model for how Tril Dampens Nodal Signaling. The Tril interacting protein, Peli2, is internalized along with Tril (1), binds to Nedd4l together with Traf6 (2), and both are required for membrane translocation and activation of Nedd4l (3). Activated Nedd4l is recruited to the Nodal receptor by Smad7 (4), and ubiquitinates it, targeting it for proteosomal degradation (5).
