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Long, Noncoding RNA SRA Induces Apoptosis of ?-Cells by Promoting the IRAK1/LDHA/Lactate Pathway.

ABSTRACT: Long non-coding RNA steroid receptor RNA activators (LncRNA SRAs) are implicated in the ?-cell destruction of Type 1 diabetes mellitus (T1D), but functional association remains poorly understood. Here, we aimed to verify the role of LncRNA SRA regulation in ?-cells. LncRNA SRAs were highly expressed in plasma samples and peripheral blood mononuclear cells (PBMCs) from T1D patients. LncRNA SRA was strongly upregulated by high-glucose treatment. LncRNA SRA acts as a microRNA (miR)-146b sponge through direct sequence-structure interactions. Silencing of lncRNA SRA increased the functional genes of Tregs, resulting in metabolic reprogramming, such as decreased lactate levels, repressed lactate dehydrogenase A (LDHA)/phosphorylated LDHA (pLDHA at Tyr10) expression, decreased reactive oxygen species (ROS) production, increased ATP production, and finally, decreased ?-cell apoptosis in vitro. There was a positive association between lactate level and hemoglobin A1c (HbA1c) level in the plasma from patients with T1D. Recombinant human interleukin (IL)-2 treatment repressed lncRNA SRA expression and activity in ?-cells. Higher levels of lncRNA-SRA/lactate in the plasma are associated with poor regulation in T1D patients. LncRNA SRA contributed to T1D pathogenesis through the inhibition of miR-146b in ?-cells, with activating signaling transduction of interleukin-1 receptor-associated kinase 1 (IRAK1)/LDHA/pLDHA. Taken together, LncRNA SRA plays a critical role in the function of ?-cells.

SUBMITTER: Huang YN

PROVIDER: S-EPMC7914996 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Long, Noncoding RNA SRA Induces Apoptosis of β-Cells by Promoting the IRAK1/LDHA/Lactate Pathway.

Huang Yu-Nan YN Chiang Shang-Lun SL Lin Yu-Jung YJ Liu Su-Ching SC Li Yen-Hsien YH Liao Yu-Chen YC Lee Maw-Rong MR Su Pen-Hua PH Tsai Fuu-Jen FJ Hung Hui-Chih HC Wang Chung-Hsing CH

International journal of molecular sciences 20210209 4

Long non-coding RNA steroid receptor RNA activators (LncRNA SRAs) are implicated in the β-cell destruction of Type 1 diabetes mellitus (T1D), but functional association remains poorly understood. Here, we aimed to verify the role of LncRNA SRA regulation in β-cells. LncRNA SRAs were highly expressed in plasma samples and peripheral blood mononuclear cells (PBMCs) from T1D patients. LncRNA SRA was strongly upregulated by high-glucose treatment. LncRNA SRA acts as a microRNA (miR)-146b sponge thro ...[more]

PMID: 33572095

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Project description:Lactate dehydrogenase A (LDHA) is a critical metabolic enzyme belonging to a family of 2-hydroxy acid oxidoreductases that plays a key role in anaerobic metabolism in the cells. In hypoxia condition, the overexpression of LDHA shifts the metabolic pathway of ATP synthesis from oxidative phosphorylation to aerobic glycolysis and the hypoxia condition is a common phenomenon occurred in the microenvironment of tumor cells; therefore, the inhibition of LDHA is considered to be an excellent strategy for cancer therapy. In this study, we employed in silico methods to design inhibitory peptides for lactate dehydrogenase through the disturbance in tetramerization of the enzyme. Using peptide as an anti-cancer agent is a novel approach for cancer therapy possessing some advantages with respect to the chemotherapeutic drugs such as low toxicity, ease of synthesis, and high target specificity. So peptides can act as appropriate enzyme inhibitor in parallel to chemical compounds. In this study, several computational techniques such as molecular dynamics (MD) simulation, docking and MM-PBSA calculation have been employed to investigate the structural characteristics of the monomer, dimer, and tetramer forms of the enzyme. Analysis of MD simulation and protein-protein interaction showed that the N-terminal arms of each subunit have an important role in enzyme tetramerization to establish active form of the enzyme. Hence, N-terminal arm can be used as a template for peptide design. Then, peptides were designed and evaluated to obtain best binders based on the affinity and physicochemical properties. Finally, the inhibitory effect of the peptides on subunit association was measured by dynamic light scattering (DLS) technique. Our results showed that the designed peptides which mimic the N-terminal arm of the enzyme can successfully target the C-terminal domain and interrupt the bona fide form of the enzyme subunits. The result of this study makes a new avenue to disrupt the assembly process and thereby oppress the function of the LDHA.

Dataset Information

Long, Noncoding RNA SRA Induces Apoptosis of ?-Cells by Promoting the IRAK1/LDHA/Lactate Pathway.

Publications

Long, Noncoding RNA SRA Induces Apoptosis of β-Cells by Promoting the IRAK1/LDHA/Lactate Pathway.

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