[en] [en] UNLABELLED: The internal ribosome entry site (IRES) element constitutes a cis-acting RNA regulatory sequence that recruits the ribosomal initiation complex in a cap-independent manner, assisted by various RNA-binding proteins and IRES trans-acting factors. Foot-and-mouth disease virus (FMDV) contains a functional IRES element and takes advantage of this element to subvert host translation machinery. Our study identified a novel mechanism wherein RALY, a member of the heterogeneous nuclear ribonucleoproteins (hnRNP) family belonging to RNA-binding proteins, binds to the domain 3 of FMDV IRES via its RNA recognition motif residue. This interaction results in the downregulation of FMDV replication by inhibiting IRES-driven translation. Furthermore, our findings reveal that the inhibitory effect exerted by RALY on FMDV replication is not attributed to the FMDV IRES-mediated assembly of translation initiation complexes but rather to the impediment of 80S ribosome complex formation after binding with 40S ribosomes. Conversely, 3Cpro of FMDV counteracts RALY-mediated inhibition by the ubiquitin-proteasome pathway. Therefore, these results indicate that RALY, as a novel critical IRES-binding protein, inhibits FMDV replication by blocking the formation of 80S ribosome, providing a deeper understanding of how viruses recruit and manipulate host factors.
IMPORTANCE: The translation of FMDV genomic RNA driven by IRES element is a crucial step for virus infections. Many host proteins are hijacked to regulate FMDV IRES-dependent translation, but the regulatory mechanism remains unknown. Here, we report for the first time that cellular RALY specifically interacts with the IRES of FMDV and negatively regulates viral replication by blocking 80S ribosome assembly on FMDV IRES. Conversely, RALY-mediated inhibition is antagonized by the viral 3C protease by the ubiquitin-proteasome pathway. These results would facilitate further understanding of virus-host interactions and translational control during viral infection.
Disciplines :
Veterinary medicine & animal health
Author, co-author :
Wu, Jin'en ; State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China ; College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu, China
Sun, Chao; Division of Livestock Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
Guan, Junyong; Division of Livestock Infectious Diseases, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
Abdullah, Sahibzada Waheed ; State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
Wang, Xuefei; State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
Ren, Mei ; Université de Liège - ULiège > TERRA Research Centre ; State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
Qiao, Lu; State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
Sun, Shiqi; State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
Guo, Huichen ; State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China ; College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu, China ; School of Animal Science, Yangtze University, Jingzhou, China ; Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
Language :
English
Title :
Nuclear ribonucleoprotein RALY downregulates foot-and-mouth disease virus replication but antagonized by viral 3C protease.
NSCF - National Natural Science Foundation of China [CN]
Funding text :
This work was supported by the National Natural Science Foundation of China (32002272, 32000126, 32072847, and 32072859), the National Key R&D Program of China (2021YFD1800300), Science and Technology Major Project of Gansu Province (21ZD3NA001), Science and Technology Talents and Platform Program (202205AF150007), and the Youth Science and Technology Fund of Gansu Province (23JRRA551).MOST | National Natural Science Foundation of China (NSFC)MOST | National Key Research and Development Program of ChinaMOST | National Natural Science Foundation of China 32002272 Jin'en Wu (NSFC) MOST | National Natural Science Foundation of China 32000126 Chao Sun (NSFC) MOST | National Natural Science Foundation of China 32072847 Huichen Guo (NSFC) MOST | National Natural Science Foundation of China 32072859 Shiqi Sun (NSFC) MOST | National Key Research and Development 2021YFD1800303 Shiqi Sun Program of China Lanzhou Talent Innovation and Entrepreneurship 2023-RC-3 Huichen Guo Project The Major Science and Technology Project of Gansu 23ZDNA007 Huichen Guo Province Youth science and technology fund of gansu province 23JRRA551 Jin'en Wu
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