Regulation of cytokine signaling through direct interaction between cytokine receptors and the ATG16L1 WD40 domain

Inmaculada Serramito-Gómez, Emilio Boada-Romero, Raquel Villamuera, Álvaro Fernández-Cabrera, José Luis Cedillo, Ángela Martín-Regalado, Simon Carding, Uli Mayer, Penny P. Powell, Thomas Wileman, Irene García-Higuera and Felipe X. Pimentel-Muiños ()
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Inmaculada Serramito-Gómez: Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca
Emilio Boada-Romero: Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca
Raquel Villamuera: Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca
Álvaro Fernández-Cabrera: Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca
José Luis Cedillo: Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca
Ángela Martín-Regalado: Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca
Simon Carding: Norwich Research Park
Uli Mayer: University of East Anglia
Penny P. Powell: University of East Anglia
Thomas Wileman: Norwich Research Park
Irene García-Higuera: Universidad Autónoma de Madrid
Felipe X. Pimentel-Muiños: Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract ATG16L1, an autophagy mediator that specifies the site of LC3 lipidation, includes a C-terminal domain formed by 7 WD40-type repeats (WD40 domain, WDD), the function of which is unclear. Here we show that the WDD interacts with the intracellular domain of cytokine receptors to regulate their signaling output in response to ligand stimulation. Using a refined version of a previously described WDD-binding amino acid motif, here we show that this element is present in the intracellular domain of cytokine receptors. Two of these receptors, IL-10RB and IL-2Rγ, recognize the WDD through the motif and exhibit WDD-dependent LC3 lipidation activity. IL-10 promotes IL-10RB/ATG16L1 interaction through the WDD, and IL-10 signaling is suboptimal in cells lacking the WDD owing to delayed endocytosis and inefficient early trafficking of IL10/IL-10R complexes. Our data reveal WDD-dependent roles of ATG16L1 in the regulation of cytokine receptor trafficking and signaling, and provide a WDD-binding motif that might be used to identify additional WDD activators.

Date: 2020
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DOI: 10.1038/s41467-020-19670-4

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