Dataset Information

ORMDL3 Functions as a Negative Regulator of Antigen-Mediated Mast Cell Activation via an ATF6-UPR-Autophagy-Dependent Pathway.

ABSTRACT: Antigen (Ag)-mediated mast cell activation plays a critical role in the immunopathology of IgE-dependent allergic diseases. Restraining the signaling cascade that regulates the release of mast cell-derived inflammatory mediators is an attractive therapeutic strategy to treat allergic diseases. Orosomucoid-like-3 (ORMDL3) regulates the endoplasmic reticulum stress (ERS)-induced unfolded protein response (UPR) and autophagy. Although ERS/UPR/autophagy pathway is crucial in Ag-induced mast cell activation, it is unknown whether ORMDL3 regulates the ERS/UPR/autophagy pathway during mast cell activation. In this study, we found that ORMDL3 expression was downregulated in Ag-activated MC/9 cells. Overexpression of ORMDL3 significantly inhibited degranulation, and cytokine/chemokine production, while the opposite effect was observed with ORMDL3 knockdown in MC/9 cells. Importantly, ORMDL3 overexpression upregulated mediators of ERS-UPR (SERCA2b, ATF6) and autophagy (Beclin 1 and LC3BII). Knockdown of ATF6 and/or inhibition of autophagy reversed the decreased degranulation and cytokine/chemokine expression caused by ORMDL3 overexpression. Moreover, in vivo knockdown of ORMDL3 and/or ATF6 enhanced passive cutaneous anaphylaxis (PCA) reactions in mouse ears. These data indicate that ORMDL3 suppresses Ag-mediated mast cell activation via an ATF6 UPR-autophagy dependent pathway and thus, attenuates anaphylactic reaction. This highlights a potential mechanism to intervene in mast cell mediated diseases.

SUBMITTER: Li J

PROVIDER: S-EPMC7933793 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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ORMDL3 Functions as a Negative Regulator of Antigen-Mediated Mast Cell Activation <i>via</i> an ATF6-UPR-Autophagy-Dependent Pathway.

Li Jia J Ullah Md Ashik MA Jin Hongping H Liang Yuting Y Lin Lihui L Wang Juan J Peng Xia X Liao Huanjin H Li Yanning Y Ge Yiqin Y Li Li L

Frontiers in immunology 20210219

Antigen (Ag)-mediated mast cell activation plays a critical role in the immunopathology of IgE-dependent allergic diseases. Restraining the signaling cascade that regulates the release of mast cell-derived inflammatory mediators is an attractive therapeutic strategy to treat allergic diseases. Orosomucoid-like-3 (ORMDL3) regulates the endoplasmic reticulum stress (ERS)-induced unfolded protein response (UPR) and autophagy. Although ERS/UPR/autophagy pathway is crucial in Ag-induced mast cell act ...[more]

PMID: 33679742

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Project description:The potassium channel protein KCNH2 is encoded by KCNH2 gene, and there are more than 300 mutations of KCNH2. Unfolded protein response (UPR) is typically initiated in response to an accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER). The present study aimed to explore the UPR process and the role of activating transcription factor 6 (ATF6) in the abnormal expression of potassium voltage-gated channel subfamily H member 2 (KCNH2)A561V. The wild-type (wt) KCNH2 and A561V mutant KCNH2 was constructed with his-tag. The 293 cells were used and divided into KCNH2wt+KCNH2A561V, KCNH2wt and KCNH2A561V groups. The expression levels of ATF6 and KCNH2 in different groups were detected by Western blotting, reverse transcription-quantitative PCR, immunofluorescence and immuno-coprecipitation assays. The protein types and abundance of immuno-coprecipitation samples were analyzed by mass spectrometry. The proteomic analysis of the mass spectrometry results was carried out by using the reactome database and GO (Gene Ontology) tool. The mRNA expression levels of KCNH2 and ATF6 in the KCNH2wt+KCNH2A561V group were higher compared with the KCNH2A561V group. However, the full-length protein expression of ATF6 was inhibited, indicating that ATF6 was highly activated and a substantial number of ATF6 was sheared in KCNH2wt+KCNH2A561V group compared with control group. Furthermore, A561V-KCNH2 mutation leading to the accumulation of the immature form of KCNH2 (135 kDa bands) in ER, resulting in the reduction of the ratio of 155 kDa/135 kDa. In addition, the abundance of UPR-related proteins in the KCNH2A561V group was higher compared with the KCNH2wt+KCNH2A561V group. The 'cysteine biosynthetic activity' of GO:0019344 process and the 'positive regulation of cytoplasmic translation activity' of GO:2000767 process in the KCNH2A561V group were higher compared with the KCNH2wt+KCNH2A561V group. Hence, co-expression of wild-type and A561V mutant KCNH2 in 293 cells activated the UPR process, which led to the inhibition of protein translation and synthesis, in turn inhibiting the expression of KCNH2. These results provided a theoretical basis for clinical treatment of Long QT syndrome.

Dataset Information

ORMDL3 Functions as a Negative Regulator of Antigen-Mediated Mast Cell Activation via an ATF6-UPR-Autophagy-Dependent Pathway.

Publications

ORMDL3 Functions as a Negative Regulator of Antigen-Mediated Mast Cell Activation <i>via</i> an ATF6-UPR-Autophagy-Dependent Pathway.

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