LncTRPM2-AS inhibits TRIM21-mediated TRPM2 ubiquitination and prevents autophagy-induced apoptosis of macrophages in asthma

Abstract

Long non-coding RNAs (lncRNAs) play a crucial role in macrophage development but little is known about their role in asthma. Here, we investigated the role of lncRNA lncTRPM2-AS in asthma and found that lncTRPM2-AS participates in the promotion of macrophage inflammation. Downregulation of lncTRPM2-AS promoted apoptosis and inhibited proliferation and production of cytokines including IL-1β, IL-4, IL-6, IL-10, TNF-α, and TGF-β. RNA-immunoprecipitation and mass spectrometry indicated that the protein TRPM2 interacted with both lncTRPM2-AS and the E3 ubiquitin ligase TRIM21. LncTRPM2-AS silencing enhanced the interaction between TRIM21 and TRPM2, resulting in elevated levels of ubiquitin-related degradation of TRPM2. Mutation analysis indicated that TRPM2 K1218 is a key site for TRIM21-dependent ubiquitination. Downregulation of lncTRPM2-AS significantly decreased intracellular calcium levels by restraining TRPM2 protein expression, which in turn decreased ROS levels and increased autophagy to promote macrophage apoptosis and reduce cytokine production, together inhibiting macrophage inflammation. Taken together, our findings demonstrate that lncTRPM2-AS blocks the ubiquitination of TRPM2 via TRIM21 and inhibits autophagy-induced apoptosis which may contribute to macrophage inflammation in asthma.

Decreased ubiquitin modifying enzyme A20 associated with hyper-responsiveness to ovalbumin challenge following intrauterine growth restriction

“…Recently, more and more studies have also identified the ubiquitination as a central process in the pathogenesis and development of asthma [ 23 , 25 ]. Ubiquitination also indirectly participated in the pathogenesis of asthma through regulating functions of macrophage and dendritic cells [ 26 , 27 ].…”

The Role of Macrophage Autophagy in Asthma: A Novel Therapeutic Strategy

“…It should be noted that autophagy also regulates macrophage apoptosis and further affects inflammation in asthma. A recent study has revealed that the lncRNA TRPM2-AS can inhibit autophagy-mediated apoptosis in macrophages by suppressing the TRIM21 (tripartite motif containing 21, an E3 ubiquitin ligase)-induced TRPM2 ubiquitination and further decreasing ROS levels, thus reducing the release of cytokines including IL-1 β , IL-4, IL-6, IL-10, TNF- α , and TGF- β in asthma [ 73 ]. These findings indicate that repression of macrophage autophagy promotes the inflammatory responses in asthma, which are associated with mitochondrial ROS accumulation.…”

A Interacting Model: How TRIM21 Orchestrates with Proteins in Intracellular Immunity

“…[67] In intracellular immunity, TRIM21 was strongly reported to modulate the stability and activity of IRFs positively or negatively via ubiquitination, reportedly including IRF3, IRF5, IRF7, and IRF8 (Figure 3). Thereby, TRIM21 indirectly influence the level of cytokines in IRFs driven way, contributing to regulation of genes such as type I IFN (IFN-𝛼, IFN-𝛽), type II IFN (IFN-𝛾), IL-6, IL12, IL-12p40, and then differentiation of immune cell, mostly containing lymphocytes, [47,[68][69][70] macrophage, [61,66,71,72] mononuclear cells, [60,73] and so on. As the historical marker of autoimmune diseases, recent studies suggested TRIM21 was overexpressed in patient with SLE and induced ubiquitination of IRF3, IRF5, and IRF7, therefore enhancing the synthesis of type I IFN.…”