Chitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2

• Published in: Cell reports (Cambridge) Vol. 4; no. 4; pp. 830 - 841
• Main Authors: He, Chuan Hua, Lee, Chun Geun, Dela Cruz, Charles S., Lee, Chang-Min, Zhou, Yang, Ahangari, Farida, Ma, Bing, Herzog, Erica L., Rosenberg, Stephen A., Li, Yue, Nour, Adel M., Parikh, Chirag R., Schmidt, Insa, Modis, Yorgo, Cantley, Lloyd, Elias, Jack A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.08.2013; Elsevier
• Subjects: Animals; Apoptosis; Chitinase-3-Like Protein 1; Glycoproteins - genetics; Glycoproteins - metabolism; Humans; Inflammasomes - metabolism; Interleukin-13 - metabolism; Interleukin-13 Receptor alpha2 Subunit - metabolism; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Macrophages - metabolism; MAP Kinase Signaling System; Melanoma - metabolism; Melanoma - secondary; Mice; Mice, Inbred C57BL; Oxidative Stress; Protein Binding; Transforming Growth Factor beta - metabolism; Wnt Signaling Pathway
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.07.032

Members of the 18 glycosyl hydrolase (GH 18) gene family have been conserved over species and time and are dysregulated in inflammatory, infectious, remodeling, and neoplastic disorders. This is particularly striking for the prototypic chitinase-like protein chitinase 3-like 1 (Chi3l1), which plays a critical role in antipathogen responses where it augments bacterial killing while stimulating disease tolerance by controlling cell death, inflammation, and remodeling. However, receptors that mediate the effects of GH 18 moieties have not been defined. Here, we demonstrate that Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2) and that Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex. We also demonstrate that Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms. Thus, IL-13Rα2 is a GH 18 receptor that plays a critical role in Chi3l1 effector responses. [Display omitted] •Chi3l1 binds to IL-13Rα2 and stimulates MAPK, Akt/PKB, and Wnt//β-catenin signaling•Chi3l1 regulates oxidant injury, apoptosis, and pyroptosis via IL-13Rα2•Chi3l1 regulates antibacterial response and inflammasome activation via IL-13Rα2•Chi3l1 regulates melanoma metastasis and TGF-β1 production via IL-13Rα2 The prototypic chitinase-like protein chitinase 3-like 1 (Chi3l1) plays critical roles in antipathogen responses where it augments bacterial killing, stimulates disease tolerance, and controls cell death, inflammation, and remodeling. However, receptors that mediate the effects of Chi3l1 or any other 18 glycosyl hydrolase gene family member have not been defined. Here, Elias and colleagues demonstrate that Chi3l1 binds to, signals, and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 via IL-13 receptor α2 (IL-13Rα2).