2. Academic Validation
  3. Pseudorabies virus gM protein and herpesvirus homologs block selective autophagy to enhance viral replication

Pseudorabies virus gM protein and herpesvirus homologs block selective autophagy to enhance viral replication

  • Autophagy. 2025 Jun 3:1-17. doi: 10.1080/15548627.2025.2511584.
Qiongqiong Zhou 1 2,  Deshi Shi 3,  Yan-Dong Tang 1 2,  Longfeng Zhang 1,  Hongyang Liu 1,  Guangqiang Ye 1,  Zhaoxia Zhang 1 2,  Boli Hu 4,  Li Huang 1 2,  Changjiang Weng 1 2
Affiliations

Affiliations

  • 1 Division of Fundamental Immunology, State Key Laboratory of Animal Disease Prevention and Control, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China.
  • 2 Heilongjiang Provincial Key Laboratory of Veterinary Immunology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China.
  • 3 State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China.
  • 4 MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, Zhejiang, China.
PMID: 40462306 DOI: 10.1080/15548627.2025.2511584
Abstract

Macroautophagy/Autophagy is a biological process that sequesters and degrades cytoplasmic material, damaged organelles, and infectious pathogens in eukaryotic cells via lysosomes. Autophagy is involved in different phases of the viral life cycle and regulates viral replication. Here, we demonstrated that pseudorabies virus (PRV) Infection induced incomplete Autophagy, and blocking the autophagosome-lysosome fusion facilitated PRV replication. Mechanistically, PRV late envelope glycoprotein M (gM) triggered SQSTM1/p62-dependent selective Autophagy. Meanwhile, gM protein was found to inhibit the fusion between autophagosomes and lysosomes by activating CASP3 (Caspase 3) to degrade SNAP29, resulting in increased viral replication. Interestingly, we confirmed that the gM homologs from several herpesviruses (herpes simplex virus-1, human cytomegalovirus, equine herpesvirus-1, and varicella-zoster virus) shared the same function of activating CASP3 and inhibiting autophagic flux. Deletion of the CASP3 gene led to an intact autophagic pathway and the increased formation of autolysosomes. Collectively, our results illustrated that blockage of autophagosome-lysosome fusion mediated by PRV gM and its homologs in Other herpesviruses protected Viral Proteins from host autophagic signaling, thus facilitating herpesvirus replication.Abbreviations: 3-MA: 3-methyladenine; Baf A1: bafilomycin A1; CASP3: Caspase 3; cl-CASP3: cleaved-CASP3; co-IP: co-immunoprecipitation; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DMSO: dimethyl sulfoxide; EHV-1: equine herpesvirus 1; gM: glycoprotein M; HCMV: human cytomegalovirus; HSV-1: herpes simplex virus 1; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; OD: optical density; PCR: polymerase chain reaction; PFU: plaque forming units; PRV: pseudorabies virus; Rap: rapamycin; SNAP29; synaptosome associated protein 29; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TCID: 50% tissue culture infectious doses; UBA: ubiquitin-binding domain; VAMP8: vesicle associated membrane protein 8; µm, micrometer; VZV: varicella-zoster virus; WT: wild type.

Keywords

Caspase 3; SNAP29; gM homologs; inhibit autophagic flux; macroautophagy; protein aggregates.

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