Tril dampens Nodal signaling through Pellino2‐ and Traf6‐mediated activation of Nedd4l

Abstract

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.