Unconventional WD40 domain-dependent role of ATG16L1 in the regulation of IL10R (interleukin 10 receptor) endocytosis, trafficking and signaling

• Published in: Autophagy 2021-09, Vol.17 (9), p.2639-2641
• Main Authors: Villamuera, Raquel, Fernández-Cabrera, Alvaro, Serramito-Gómez, Inmaculada, Terraza-Silvestre, Elena, Taouil, Rachid, Pimentel-Muiños, Felipe X.
• Format: Article
• Language: English
• Subjects: ATG16L1; Autophagic Punctum; Autophagy - physiology; Autophagy-Related Proteins - metabolism; cytokine receptor trafficking; cytokine signaling; Endocytosis; IL10R endocytosis and signaling; Receptors, Interleukin-10; unconventional autophagy; WD40 domain; WD40 Repeats
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2021.1947606

ATG16L1 is a critical mediator of macroautophagy/autophagy required for LC3 lipidation and autophagosome formation. However, ATG16L1 has a C-terminal domain including 7 WD40-type repetitions (WD40 domain, WDD) that is unnecessary for the conventional autophagic pathway. Instead, this domain mediates unconventional activities where LC3 is lipidated in atypical subcellular localizations unrelated to canonical double-membrane autophagosomes. The WDD provides a docking surface for molecules including a specific amino acid motif, thus engaging the LC3 lipidation capabilities of ATG16L1 in single-membrane structures. The physiological implications of such atypical activities are poorly characterized. In a recent report we described the improvement of the WDD-binding motif and the identification of transmembrane molecules that harbor this element in their intracellular region. One of them, IL10RB (interleukin 10 receptor subunit beta), binds the WDD after IL10 activation to facilitate endocytosis, early trafficking and signaling of IL10-IL10R complexes without influencing their degradation rate. These results reveal a novel unconventional role of ATG16L1 in cytokine signaling that does not entail a degradative purpose, thus contributing to catalog the physiological roles played by unconventional activities of the autophagic machinery.