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A Previously Undiscovered Circular RNA, circTNFAIP3, and Its Role in Coronavirus Replication.

ABSTRACT: Circular RNAs (circRNAs) are a newly discovered class of noncoding RNAs (ncRNAs) present in various tissues and cells. However, the functions of most circRNAs have not been verified experimentally. Here, using deltacoronavirus as a model, differentially expressed circRNAs in cells with or without deltacoronavirus infection were analyzed by RNA sequencing to characterize the cellular responses to RNA virus infection. More than 57,000 circRNA candidates were detected, and seven significantly dysregulated circRNAs were quantitated by real-time reverse transcription-PCR. We discovered a previously unidentified circRNA derived from the TNFAIP3 gene, named circTNFAIP3, which is distributed and expressed widely in various tissues. RNA viruses, including deltacoronaviruses, rather than DNA viruses tend to activate the expression of endogenous circTNFAIP3. Overexpression of circTNFAIP3 promoted deltacoronavirus replication by reducing the apoptosis, while silencing of circTNFAIP3 inhibited deltacoronavirus replication by enhancing the apoptosis. In summary, our work provides useful circRNA-related information to facilitate investigation of the underlying mechanism of deltacoronavirus infection and identifies a novel circTNFAIP3 that promotes deltacoronavirus replication via regulating apoptosis. IMPORTANCE CircRNAs, a new class of ncRNAs, play important roles in cell growth, neural development, carcinogenesis, and anticarcinogenesis. Porcine deltacoronavirus is an emerging enteropathogenic coronavirus that causes diarrhea, but the role of host circRNAs in regulating its infection is unknown. Here, we performed expression profiling of circRNAs in mock- and deltacoronavirus- infected cells and identified the novel differentially expressed circular RNA circTNFAIP3. We demonstrate that circTNFAIP3 promotes deltacoronavirus replication by inhibiting apoptosis. Our findings first illustrate that circRNA can act as an apoptosis negative regulator during RNA virus infection and help to explore the underlying mechanism of deltacoronavirus infection.

SUBMITTER: Du L

PROVIDER: S-EPMC8593679 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCircular RNAs (circRNAs) are RNA transcripts that are widespread in the eukaryotic genome. Recent evidence indicates that circRNAs play important roles in tissue development, gene regulation, and carcinogenesis. However, whether circRNAs encode functional proteins remains elusive, although translation of several circRNAs was recently reported.MethodsCircRNA deep sequencing was performed by using 10 pathologically diagnosed glioblastoma samples and their paired adjacent normal brain tissues. Northern blotting, Sanger sequencing, antibody, and liquid chromatograph Tandem Mass Spectrometer were used to confirm the existence of circ-FBXW7 and its encoded protein in in two cell lines. Lentivirus-transfected stable U251 and U373 cells were used to assess the biological functions of the novel protein invitro and invivo (five mice per group). Clinical implications of circ-FBXW7 were assessed in 38 pathologically diagnosed glioblastoma samples and their paired periphery normal brain tissues by using quantitative polymerase chain reaction (two-sided log-rank test).ResultsCirc-FBXW7 is abundantly expressed in the normal human brain (reads per kilobase per million mapped reads [RPKM] = 9.31). The spanning junction open reading frame in circ-FBXW7 driven by internal ribosome entry site encodes a novel 21-kDa protein, which we termed FBXW7-185aa. Upregulation of FBXW7-185aa in cancer cells inhibited proliferation and cell cycle acceleration, while knockdown of FBXW7-185aa promoted malignant phenotypes invitro and invivo. FBXW7-185aa reduced the half-life of c-Myc by antagonizing USP28-induced c-Myc stabilization. Moreover, circ-FBXW7 and FBXW7-185aa levels were reduced in glioblastoma clinical samples compared with their paired tumor-adjacent tissues (P < .001). Circ-FBXW7 expression positively associated with glioblastoma patient overall survival (P = .03).ConclusionsEndogenous circRNA encodes a functional protein in human cells, and circ-FBXW7 and FBXW7-185aa have potential prognostic implications in brain cancer.

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A Previously Undiscovered Circular RNA, circTNFAIP3, and Its Role in Coronavirus Replication.

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