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

• Published in: Nature communications 2020-11, Vol.11 (1), p.5919-5919, Article 5919
• Main Authors: Serramito-Gómez, Inmaculada, Boada-Romero, Emilio, Villamuera, Raquel, Fernández-Cabrera, Álvaro, Cedillo, José Luis, Martín-Regalado, Ángela, Carding, Simon, Mayer, Uli, Powell, Penny P., Wileman, Thomas, García-Higuera, Irene, Pimentel-Muiños, Felipe X.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/21; 13/95; 14; 14/19; 38/77; 631/250/127/1213; 631/80/39/2346; 631/80/86; 82/75; 82/79; 96/95; Amino acids; Autophagy; Autophagy - physiology; Autophagy-Related Proteins - metabolism; Binding; Carrier Proteins - metabolism; Cytokine receptors; Cytokines; Cytokines - chemistry; Cytokines - metabolism; Domains; Endocytosis; Endocytosis - physiology; Humanities and Social Sciences; Humans; Interleukin 1; Interleukin 10; Interleukin 2 receptors; Interleukin-10 - metabolism; Intracellular; Intracellular signalling; Microtubule-Associated Proteins - metabolism; multidisciplinary; Peptide libraries; Phagocytosis; Protein Transport; Receptors; Receptors, Cytokine - metabolism; Receptors, Interleukin-10 - metabolism; Science; Science (multidisciplinary); Signal Transduction - physiology; Signaling; WD40 Repeats
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19670-4

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. The WD40 domain of ATG16L1 is thought to be involved in non-canonical autophagy. Here the authors screen peptide libraries and identify interactions between this domain and the IL-2Rγ and IL-10RB receptors, indicating endosomal regulation of cytokine signalling by non-canonical autophagy.