2. Academic Validation
  3. The ubiquitin conjugating enzyme E2 F (UBE2F)-RING-box protein 2 (RBX2)-mediated neddylation of Cullin5 facilitates pseudorabies virus replication

The ubiquitin conjugating enzyme E2 F (UBE2F)-RING-box protein 2 (RBX2)-mediated neddylation of Cullin5 facilitates pseudorabies virus replication

  • Int J Biol Macromol. 2025 Dec 30:150018. doi: 10.1016/j.ijbiomac.2025.150018.
Zhiyuan Zheng 1,  Fei Zhao 1,  Senhong Zhao 1,  Yaning Bai 1,  Lunwen Shi 1,  Binbin Zhu 1,  Xiaobo Huang 1,  Yi Zheng 1,  Qin Zhao 1,  Yiping Wen 1,  Rui Wu 1,  Senyan Du 1,  Sanjie Cao 1,  Qigui Yan 1,  Zhiwen Xu 2,  Scott A Tibbetts 3,  Yiping Wang 4
Affiliations

Affiliations

  • 1 Department of Preventive Veterinary Medicine, Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, 611130, China.
  • 2 Animal Biotechnology Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, 611130, China.
  • 3 Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida, 32610, USA.
  • 4 Department of Preventive Veterinary Medicine, Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, 611130, China; Key Laboratory of Agricultural Bioinformatics of Ministry of Education, Sichuan Agricultural University, Chengdu, 611130, China. Electronic address: [email protected].
PMID: 41478481 DOI: 10.1016/j.ijbiomac.2025.150018
Abstract

Pseudorabies virus (PRV) is an important swine herpesvirus that causes fatal encephalitis in newborn piglets and severe reproductive failure in pregnant sows, resulting in enormous economic losses in the pig industry worldwide. It has broad cell tropisms with the capability to infect a wide range of Animals, including humans, thus posing a potential threat to human health. Neddylation is an important protein posttranslational modification that is catalyzed by an E1-E2-E3 enzyme cascade to covalently conjugate the ubiquitin-like molecule neural precursor cell expressed developmentally downregulated 8 (NEDD8) to substrate proteins. It has been demonstrated to play a key role in regulating numerous important biological processes, including cell proliferation, gene expression, signal transduction, and viral Infection. However, the specific function of the neddylation pathway during PRV Infection remains largely unknown. In the work described here, we identified a critically important role for neddylation in PRV replication by utilizing short hairpin RNA (shRNA)-mediated depletion of NEDD8 or the NEDD8-activating Enzyme E1 subunit 1 (NAE1). Through systematic investigation of E2-E3 neddylation partners, we further demonstrated that silencing of the ubiquitin conjugating enzyme E2 F (UBE2F)-RING-box protein 2 (RBX2) axis significantly decreased PRV replication. Furthermore, knockdown of the neddylation substrate Cullin5 (CUL5) or pharmacological inhibition of CUL5 neddylation significantly attenuated PRV replication. Cumulatively, these findings demonstrate that the UBE2F-RBX2-mediated neddylation of CUL5 facilitates PRV replication. This study provides a new theoretical basis for in-depth understanding of PRV-host interaction and reveals neddylation as a novel target for Antiviral strategies against PRV.

Keywords

Cullin5; Neddylation; Pseudorabies virus; RBX2; UBE2F; Virus replication.

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