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XB-ART-58424
Proc Natl Acad Sci U S A September 7, 2021; 118 (36):
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Tril dampens Nodal signaling through Pellino2- and Traf6-mediated activation of Nedd4l.

Kim HS , Green YS , Xie Y , Christian JL .


Abstract
Toll-like receptor 4 (Tlr) interactor with leucine-rich repeats (Tril) functions as a Tlr coreceptor to mediate innate immunity in adults. In Xenopus embryos, Tril triggers degradation of the transforming growth factor β (Tgf-ß) 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 NEDD4 Like (Nedd4l). Nedd4l then targets Nodal receptors for degradation. How Tril signals are transduced in a nonimmune 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, TNF-receptor associated factor 6 (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 noncanonical Tlr-like signaling cascade to activate Nedd4l, thereby coordinately regulating the Bmp and Nodal arms of the Tgf-ß superfamily during vertebrate development.

PubMed ID: 34475212
PMC ID: PMC8433579
Article link: Proc Natl Acad Sci U S A


Species referenced: Xenopus laevis
Genes referenced: dvl1 gsc lgr5 nedd4l nodal1 peli2 smad7 tbxt tlr3 tlr4 traf6 tril wnt8a
GO keywords: sodium channel activity [+]
Antibodies: Acta1 Ab6 FLAG Ab3 HA Ab4 Myc Ab3 Nedd4l Ab1 Peli Ab1 Tril Ab1
Morpholinos: nedd4l MO2 tril MO1 tril MO2


Article Images: [+] show captions