Dataset Information

IL-13R?2 uses TMEM219 in chitinase 3-like-1-induced signalling and effector responses.

ABSTRACT: Recent studies demonstrated that chitinase 3-like-1 (Chi3l1) binds to and signals via IL-13R?2. However, the mechanism that IL-13R?2 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-13R?2 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-13R?2-Chi3l1 complexes. Null mutations or siRNA silencing of TMEM219 or IL-13R?2 similarly decreased Chi3l1-stimulated epithelial cell HB-EGF production and macrophage MAPK/Erk and PKB/Akt activation. Null mutations of TMEM219 or IL-13R?2 also phenocopied one another as regards the ability of Chi3l1 to inhibit oxidant-induced apoptosis and lung injury, promote melanoma metastasis and stimulate TGF-?1. TMEM219 also contributed to the decoy function of IL-13R?2. These studies demonstrate that TMEM219 plays a critical role in Chi3l1-induced IL-13R?2 mediated signalling and tissue responses.

SUBMITTER: Lee CM

PROVIDER: S-EPMC5027616 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Lee Chang-Min CM He Chuan Hua CH Nour Adel M AM Zhou Yang Y Ma Bing B Park Jin Wook JW Kim Kyung Hee KH Dela Cruz Charles C Sharma Lokesh L Nasr Mahmoud L ML Modis Yorgo Y Lee Chun Geun CG Elias Jack A JA

Nature communications 20160915

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 ...[more]

PMID: 27629921

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Project description:We have shown that manipulation of IL-13 and STAT6 signaling at the vaccination site can lead to different innate lymphoid cell (ILC)/dendritic cell (DC) recruitment, resulting in high avidity/poly-functional T cells and effective antibody differentiation. Here we show that permanent versus transient blockage of IL-13 and STAT6 at the vaccination site can lead to unique ILC-derived IL-13 and IFN-γ profiles, and differential IL-13Rα2, type I and II IL-4 receptor regulation on ILC. Specifically, STAT6-/- BALB/c mice given fowl pox virus (FPV) expressing HIV antigens induced elevated ST2/IL-33R+ ILC2-derived IL-13 and reduced NKp46+/- ILC1/ILC3-derived IFN-γ expression, whilst the opposite (reduced IL-13 and elevated IFN-γ expression) was observed during transient inhibition of STAT6 signaling in wild type BALB/c mice given FPV-HIV-IL-4R antagonist vaccination. Interestingly, disruption/inhibition of STAT6 signaling considerably impacted IL-13Rα2 expression by ST2/IL-33R+ ILC2 and NKp46- ILC1/ILC3, unlike direct IL-13 inhibition. Consistently with our previous findings, this further indicated that inhibition of STAT6 most likely promoted IL-13 regulation via IL-13Rα2. Moreover, the elevated ST2/IL-33R+ IL-13Rα2+ lung ILC2, 24 h post FPV-HIV-IL-4R antagonist vaccination was also suggestive of an autocrine regulation of ILC2-derived IL-13 and IL-13Rα2, under certain conditions. Knowing that IL-13 can modulate IFN-γ expression, the elevated expression of IFN-γR on lung ST2/IL-33R+ ILC2 provoked the notion that there could also be inter-regulation of lung ILC2-derived IL-13 and NKp46- ILC1/ILC3-derived IFN-γ via their respective receptors (IFN-γR and IL-13Rα2) at the lung mucosae early stages of vaccination. Intriguingly, under different IL-13 conditions differential regulation of IL-13/IL-13Rα2 on lung DC was also observed. Collectively these findings further substantiated that IL-13 is the master regulator of, not only DC, but also different ILC subsets at early stages of viral vector vaccination, and responsible for shaping the downstream adaptive immune outcomes. Thus, thoughtful selection of vaccine strategies/adjuvants that can manipulate IL-13Rα2, and STAT6 signaling at the ILC/DC level may prove useful in designing more efficacious vaccines against different/chronic pathogens.

Dataset Information

IL-13R?2 uses TMEM219 in chitinase 3-like-1-induced signalling and effector responses.

Publications

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

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