IL-13Rα2 uses TMEM219 in chitinase 3-like-1-induced signalling and effector responses

• Published in: Nature communications Vol. 7; no. 1; pp. 12752 - 13
• Main Authors: Lee, Chang-Min, He, Chuan Hua, Nour, Adel M., Zhou, Yang, Ma, Bing, Park, Jin Wook, Kim, Kyung Hee, Cruz, Charles Dela, Sharma, Lokesh, Nasr, Mahmoud L., Modis, Yorgo, Lee, Chun Geun, Elias, Jack A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.09.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/109; 13/2; 13/21; 13/31; 13/89; 38; 38/111; 42; 631/250/127/1213; 631/250/1933; 82; 82/83; Animals; Apoptosis; Cell Line, Tumor; Chitinase-3-Like Protein 1 - metabolism; Heparin-binding EGF-like Growth Factor - metabolism; Humanities and Social Sciences; Humans; Interleukin-13 Receptor alpha2 Subunit - metabolism; Lung Injury - metabolism; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; MAP Kinase Signaling System; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Membrane Proteins - metabolism; Mice, Inbred C57BL; multidisciplinary; Neoplasm Metastasis; Proto-Oncogene Proteins c-akt - metabolism; Science; Science (multidisciplinary); Transforming Growth Factor beta1 - metabolism; Two-Hybrid System Techniques; Wnt Signaling Pathway
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12752

Recent studies demonstrated that chitinase 3-like-1 (Chi3l1) binds to and signals via IL-13Rα2. However, the mechanism that IL-13Rα2 uses to mediate the effects of Chi3l1 has not been defined. Here, we demonstrate that the membrane protein, TMEM219, is a binding partner of IL-13Rα2 using yeast two-hybrid, co-immunoprecipitation, co-localization and bimolecular fluorescence complementation assays. Furthermore, fluorescence anisotropy nanodisc assays revealed a direct physical interaction between TMEM219 and IL-13Rα2-Chi3l1 complexes. Null mutations or siRNA silencing of TMEM219 or IL-13Rα2 similarly decreased Chi3l1-stimulated epithelial cell HB-EGF production and macrophage MAPK/Erk and PKB/Akt activation. Null mutations of TMEM219 or IL-13Rα2 also phenocopied one another as regards the ability of Chi3l1 to inhibit oxidant-induced apoptosis and lung injury, promote melanoma metastasis and stimulate TGF-β1. TMEM219 also contributed to the decoy function of IL-13Rα2. These studies demonstrate that TMEM219 plays a critical role in Chi3l1-induced IL-13Rα2 mediated signalling and tissue responses. Chitinase 3-like 1 regulates cell death, inflammation and tissue remodelling via IL-13receptorα2. Here, the authors show that TMEM219 is a IL-13Rα2 co-receptor and modulates oxidant-induced apoptosis and lung injury, melanoma metastasis and TGF-β1 signalling, downstream of Chi3l1-IL-13Rα2.