LincR-PPP2R5C Promotes Th2 Cell Differentiation Through PPP2R5C/PP2A by Forming an RNA-DNA Triplex in Allergic Asthma

Overview

Journal Allergy Asthma Immunol Res

Date 2024 Jan 23

PMID 38262392

Authors

Ningfei Ji

Zhongqi Chen

Zhengxia Wang

Wei Sun

Qi Yuan

Xijie Zhang

Xinyu Jia

Jingjing Wu

Jingxian Jiang

Meijuan Song

Tingting Xu

Yanan Liu

Qiyun Ma

Zhixiao Sun

Yanmin Bao

Mingshun Zhang

Mao Huang

Affiliations

Soon will be listed here.

Abstract

Purpose: The roles and mechanisms of long noncoding RNAs (lncRNAs) in T helper 2 (Th2) differentiation from allergic asthma are poorly understood. We aimed to explore a novel lncRNA, LincR-protein phosphatase 2 regulatory subunit B' gamma (PPP2R5C), in Th2 differentiation in a mouse model of asthma.

Methods: LincR-PPP2R5C from RNA-seq data of CD4 T cells of asthma-like mice were validated and confirmed by quantitative reverse transcription polymerase chain reaction, northern blotting, nuclear and cytoplasmic separation, and fluorescence hybridization (FISH). Lentiviruses encoding LincR-PPP2R5C or shRNA were used to overexpress or silence LincR-PPP2R5C in CD4 T cells. The interactions between LincR-PPP2R5C and PPP2R5C were explored with western blotting, chromatin isolation by RNA purification assay, and fluorescence resonance energy transfer. An ovalbumin-induced acute asthma model in knockout (KO) mice (LincR-PPP2R5C KO, CD4 conditional LincR-PPP2R5C KO) was established to explore the roles of LincR-PPP2R5C in Th2 differentiation.

Results: LncR-PPP2R5C was significantly higher in CD4 T cells from asthmatic mice and Th2 cells . The lentivirus encoding LincR-PPP2R5C suppressed Th1 differentiation; in contrast, the short hairpin RNA (shRNA) lentivirus decreased LincR-PPP2R5C and Th2 differentiation. Mechanistically, LincR-PPP2R5C deficiency suppressed the phosphatase activity of the protein phosphatase 2A (PP2A) holocomplex, resulting in a decline in Th2 differentiation. The formation of an RNA-DNA triplex between LincR-PPP2R5C and the PPP2R5C promoter enhanced PPP2R5C expression and activated PP2A. LincR-PPP2R5C KO and CD4 conditional KO decreased Th2 differentiation, airway hyperresponsiveness and inflammatory responses.

Conclusions: LincR-PPP2R5C regulated PPP2R5C expression and PP2A activity by forming an RNA-DNA triplex with the PPP2R5C promoter, leading to Th2 polarization in a mouse model of acute asthma. Our data presented the first definitive evidence of lncRNAs in the regulation of Th2 cells in asthma.

Citing Articles

LincR-PPP2R5C Deficiency Alleviates Airway Remodeling by Inhibiting Epithelial-Mesenchymal Transition Through the PP2A/TGF-β1 Signaling Pathway in Chronic Experimental Allergic Asthma.

Yuan Q, Jia X, Wang M, Chen Z, Xu T, Zhang X Allergy Asthma Immunol Res. 2024; 16(4):422-433.

PMID: 39155740 PMC: 11331192. DOI: 10.4168/aair.2024.16.4.422.

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