A Fish MDA5 Integrates Canonical RIG-I and MDA5 Ligand Recognition.
- 1State Key Laboratory of Mariculture Breeding, Key Laboratory of Marine Biotechnology of Fujian Province, College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou, China.
- 2Grupo de investigación en acuicultura (GIA), IU-ECOAQUA, Universidad De Las Palmas De Gran Canaria, Las Palmas, Spain.
- 3College of Biomedical Sciences, Fujian Agriculture and Forestry University, Fuzhou, China.
Abstract
RIG-I and MDA5 are cytosolic RNA sensors that recognize distinct viral ligands in mammals, yet RIG-I has been independently lost from multiple teleost lineages. How RIG-I-deficient vertebrates preserve recognition of RIG-I-associated viral RNA remains poorly understood. Here, we show that MDA5 from the large yellow croaker (Larimichthys crocea, Lc), a teleost species lacking RIG-I, recognizes both 5'-triphosphate dsRNA (5'ppp-dsRNA), the canonical ligand of RIG-I, and long dsRNA, the classical ligand of MDA5. Its C-terminal domain (CTD) is essential for the recognition of both ligands, with residues specifically required for sensing the 5'ppp moiety. Structural modeling, molecular dynamics simulations, and mutational validation support a model in which a flexible RNA-capping loop in the CTD confers LcMDA5 a conformational plasticity, allowing the CTD to cap the 5'ppp-dsRNA terminus for RIG-I-like recognition or orienting the CTD parallel to long-dsRNA axis for canonical MDA5 recognition. Disruption of 5'ppp recognition impaired LcMDA5-mediated antiviral activity against a RIG-I-sensitive virus. Downstream, LcMDA5 signals through an integrated MAVS-STING-TBK1/IRF3 axis to drive type I IFN responses to both RNA ligands. Our findings reveal an unexpectedly flexible architecture of vertebrate cytosolic RNA sensing in which a single RLR combines ligand-recognition and signaling properties classically partitioned between RIG-I and MDA5.
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BibTeX
@article{li2026fish,
title = {{A Fish MDA5 Integrates Canonical RIG-I and MDA5 Ligand Recognition.}},
author = {Wenxing Li and Yuan Feng and Huazhi Chen and Jiamei Liu and Álvaro Fernández Montero and Jiangtao Gao and Jingqun Ao and Xinhua Chen},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = oct,
doi = {10.1002/advs.78318},
url = {https://europepmc.org/article/MED/42875852},
note = {CC BY},
}
RIS
TY - JOUR
TI - A Fish MDA5 Integrates Canonical RIG-I and MDA5 Ligand Recognition.
AU - Wenxing Li
AU - Yuan Feng
AU - Huazhi Chen
AU - Jiamei Liu
AU - Álvaro Fernández Montero
AU - Jiangtao Gao
AU - Jingqun Ao
AU - Xinhua Chen
PY - 2026
DA - 2026/10/14
JO - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO - 10.1002/advs.78318
UR - https://europepmc.org/article/MED/42875852
AB - RIG-I and MDA5 are cytosolic RNA sensors that recognize distinct viral ligands in mammals, yet RIG-I has been independently lost from multiple teleost lineages. How RIG-I-deficient vertebrates preserve recognition of RIG-I-associated viral RNA remains poorly understood. Here, we show that MDA5 from the large yellow croaker (Larimichthys crocea, Lc), a teleost species lacking RIG-I, recognizes both 5'-triphosphate dsRNA (5'ppp-dsRNA), the canonical ligand of RIG-I, and long dsRNA, the classical ligand of MDA5. Its C-terminal domain (CTD) is essential for the recognition of both ligands, with residues specifically required for sensing the 5'ppp moiety. Structural modeling, molecular dynamics simulations, and mutational validation support a model in which a flexible RNA-capping loop in the CTD confers LcMDA5 a conformational plasticity, allowing the CTD to cap the 5'ppp-dsRNA terminus for RIG-I-like recognition or orienting the CTD parallel to long-dsRNA axis for canonical MDA5 recognition. Disruption of 5'ppp recognition impaired LcMDA5-mediated antiviral activity against a RIG-I-sensitive virus. Downstream, LcMDA5 signals through an integrated MAVS-STING-TBK1/IRF3 axis to drive type I IFN responses to both RNA ligands. Our findings reveal an unexpectedly flexible architecture of vertebrate cytosolic RNA sensing in which a single RLR combines ligand-recognition and signaling properties classically partitioned between RIG-I and MDA5.
SN - 2198-3844
ER -