Circular RNA MARCH3 promotes influenza A virus replication by coordinating NF-κB negative feedback and the miR-3657/ATG7 axis
4 affiliations
- 1Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Science, Fujian Agriculture and Forestry University
- 2Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Science, Fujian Agriculture and Forestry University
- 3Joint Laboratory of Animal Pathogen Prevention and Control of Fujian-Nepal, College of Animal Science, Fujian Agriculture and Forestry University
- 4Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center
Abstract
Introduction: Circular RNAs (circRNAs) have emerged as important regulators of diverse cellular processes, and accumulating evidence indicates that certain circRNAs modulate immune responses through complex mechanisms. However, their roles in innate immunity against influenza A virus (IAV) infection remain poorly understood.
Methods: We identified a previously uncharacterized circRNA, termed circMARCH3, through RNA-seq, RNase R digestion assay, and RNA stability assay. We examined circMARCH3 expression in multiple cell types following viral infection by RT-PCR and real-time PCR, investigated the signaling pathway driving its induction, and performed functional analyses using circMARCH3 overexpression vectors and shRNAs-mediated knockdown. Furthermore, we identified and validated the circMARCH3/miR-3657/ATG7 axis through mechanistic studies.
Results: circMARCH3 is generated from the pre-mRNA of the membrane-associated RING-CH-Type Finger 3 (MARCH3) gene, and its expression was robustly induced by IAV and several other viral infections in multiple cell types. Mechanistically, virus-induced circMARCH3 expression was driven by the NF-κB signaling pathway. Functional analyses demonstrated that circMARCH3 overexpression significantly promoted IAV replication, whereas circMARCH3 knockdown markedly inhibited viral production. Consistent with these findings, circMARCH3 functioned as a negative regulator of antiviral innate immunity by attenuating NF-κB activation and type I interferon responses. Furthermore, we identified that circMARCH3 targeted miR-3657, a microRNA that suppresses the expression of ATG7, a key autophagy regulator and known pro-IAV factor. Mechanistic studies revealed that circMARCH3 acted as a competitive endogenous RNA (ceRNA), sequestering miR-3657 and thereby relieving its repressive effect on ATG7 expression, resulting in enhanced autophagy and increased viral replication.
Discussion: The results demonstrate circMARCH3 as a virus-inducible circRNA that promotes IAV infection through two complementary mechanisms: dampening NF-κB-mediated antiviral innate immunity and facilitating autophagy via the circMARCH3/miR-3657/ATG7 axis. Our findings establish circMARCH3 as a novel regulator of the complex interaction between host and IAV by coordinating NF-κB negative feedback and the miR-3657/ATG7 axis.
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BibTeX
@article{liu2026circular,
title = {{Circular RNA MARCH3 promotes influenza A virus replication by coordinating NF-κB negative feedback and the miR-3657/ATG7 axis}},
author = {Jiayin Liu and Jiarong Song and Ling’en Yang and Mohamed Maarouf and Haori Qiu and Shasha Liu and Shile Huang and Song Wang and Ji-Long Chen},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1948323},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1948323/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Circular RNA MARCH3 promotes influenza A virus replication by coordinating NF-κB negative feedback and the miR-3657/ATG7 axis
AU - Jiayin Liu
AU - Jiarong Song
AU - Ling’en Yang
AU - Mohamed Maarouf
AU - Haori Qiu
AU - Shasha Liu
AU - Shile Huang
AU - Song Wang
AU - Ji-Long Chen
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1948323
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1948323/full
AB - Introduction: Circular RNAs (circRNAs) have emerged as important regulators of diverse cellular processes, and accumulating evidence indicates that certain circRNAs modulate immune responses through complex mechanisms. However, their roles in innate immunity against influenza A virus (IAV) infection remain poorly understood. Methods: We identified a previously uncharacterized circRNA, termed circMARCH3, through RNA-seq, RNase R digestion assay, and RNA stability assay. We examined circMARCH3 expression in multiple cell types following viral infection by RT-PCR and real-time PCR, investigated the signaling pathway driving its induction, and performed functional analyses using circMARCH3 overexpression vectors and shRNAs-mediated knockdown. Furthermore, we identified and validated the circMARCH3/miR-3657/ATG7 axis through mechanistic studies. Results: circMARCH3 is generated from the pre-mRNA of the membrane-associated RING-CH-Type Finger 3 (MARCH3) gene, and its expression was robustly induced by IAV and several other viral infections in multiple cell types. Mechanistically, virus-induced circMARCH3 expression was driven by the NF-κB signaling pathway. Functional analyses demonstrated that circMARCH3 overexpression significantly promoted IAV replication, whereas circMARCH3 knockdown markedly inhibited viral production. Consistent with these findings, circMARCH3 functioned as a negative regulator of antiviral innate immunity by attenuating NF-κB activation and type I interferon responses. Furthermore, we identified that circMARCH3 targeted miR-3657, a microRNA that suppresses the expression of ATG7, a key autophagy regulator and known pro-IAV factor. Mechanistic studies revealed that circMARCH3 acted as a competitive endogenous RNA (ceRNA), sequestering miR-3657 and thereby relieving its repressive effect on ATG7 expression, resulting in enhanced autophagy and increased viral replication. Discussion: The results demonstrate circMARCH3 as a virus-inducible circRNA that promotes IAV infection through two complementary mechanisms: dampening NF-κB-mediated antiviral innate immunity and facilitating autophagy via the circMARCH3/miR-3657/ATG7 axis. Our findings establish circMARCH3 as a novel regulator of the complex interaction between host and IAV by coordinating NF-κB negative feedback and the miR-3657/ATG7 axis.
SN - 1664-3224
ER -