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Micropeptide AF127577.4-ORF 隐藏在长链非编码 RNA 中，通过调节 ERK2/METTL3 相互作用来抑制神经胶质瘤细胞增殖。

Micropeptide AF127577.4-ORF hidden in a lncRNA diminishes glioblastoma cell proliferation via the modulation of ERK2/METTL3 interaction.

机构信息

Department of Neurosurgery, Xinxiang Central Hospital, Xinxiang, 453003, Henan, People's Republic of China.

Department of Pathology, Xinxiang Medical University, No. 601 Jinsui Avenue, Xinxiang, 453003, Henan, People's Republic of China.

出版信息

Sci Rep. 2024 May 27;14(1):12090. doi: 10.1038/s41598-024-62710-y.

DOI:10.1038/s41598-024-62710-y
PMID:38802444
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11130299/
Abstract

Micropeptides hidden in long non-coding RNAs (lncRNAs) have been uncovered to program various cell-biological changes associated with malignant transformation-glioblastoma (GBM) cascade. Here, we identified and characterized a novel hidden micropeptide implicated in GBM. We screened potential candidate lncRNAs by establishing a workflow involving ribosome-bound lncRNAs, publicly available MS/MS data, and prognosis-related lncRNAs. Micropeptide expression was detected by western blot (WB), immunofluorescence (IF), and immunohistochemistry (IHC). Cell proliferation rate was assessed by calcein/PI staining and EdU assay. Proteins interacted with the micropeptide were analyzed by proteomics after co-immunoprecipitation (Co-IP). We discovered that lncRNA AF127577.4 indeed encoded an endogenous micropeptide, named AF127577.4-ORF. AF127577.4-ORF was associated with GBM clinical grade. In vitro, AF127577.4-ORF could suppress GBM cell proliferation. Moreover, AF127577.4-ORF reduced m6A methylation level of GBM cells. Mechanistically, AF127577.4-ORF diminished ERK2 interaction with m6A reader methyltransferase like 3 (METTL3) and downregulated phosphorylated ERK (p-ERK) level. The ERK inhibitor reduced p-ERK level and downregulated METTL3 protein expression. AF127577.4-ORF weakened the stability of METTL3 protein by ERK. Also, AF127577.4-ORF suppressed GBM cell proliferation via METTL3. Our study identifies a novel micropeptide AF127577.4-ORF hidden in a lncRNA, with a potent anti-proliferating function in GBM by diminishing METTL3 protein stability by reducing the ERK2/METTL3 interaction. This micropeptide may be beneficial for development of therapeutic strategies against GBM.

摘要

隐藏在长非编码 RNA（lncRNA）中的微肽已被发现可调控与恶性转化-胶质母细胞瘤（GBM）级联相关的各种细胞生物学变化。在这里，我们鉴定并表征了一种新型隐藏微肽，其与 GBM 相关。我们通过建立一个包含核糖体结合 lncRNA、公开可用的 MS/MS 数据和与预后相关的 lncRNA 的工作流程，筛选潜在的候选 lncRNA。通过 Western blot（WB）、免疫荧光（IF）和免疫组织化学（IHC）检测微肽表达。通过钙黄绿素/PI 染色和 EdU 测定评估细胞增殖率。通过共免疫沉淀（Co-IP）后的蛋白质组学分析，研究与微肽相互作用的蛋白质。我们发现 lncRNA AF127577.4 确实编码一种内源性微肽，命名为 AF127577.4-ORF。AF127577.4-ORF 与 GBM 临床分级相关。在体外，AF127577.4-ORF 可抑制 GBM 细胞增殖。此外，AF127577.4-ORF 降低了 GBM 细胞的 m6A 甲基化水平。机制上，AF127577.4-ORF 减少了 ERK2 与 m6A 阅读器甲基转移酶样 3（METTL3）的相互作用，并下调了磷酸化 ERK（p-ERK）水平。ERK 抑制剂降低了 p-ERK 水平并下调了 METTL3 蛋白表达。AF127577.4-ORF 通过 ERK 减弱了 METTL3 蛋白的稳定性。此外，AF127577.4-ORF 通过降低 METTL3 蛋白稳定性抑制 GBM 细胞增殖。我们的研究鉴定了一种新型微肽 AF127577.4-ORF，其隐藏在 lncRNA 中，通过降低 ERK2/METTL3 相互作用减少 METTL3 蛋白稳定性，在 GBM 中具有强大的抗增殖功能。这种微肽可能有利于开发针对 GBM 的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e93/11130299/95bf2fc3e761/41598_2024_62710_Fig7_HTML.jpg
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