The African swine fever virus MGF360-16R protein functions as a mitochondrial-dependent apoptosis inducer by competing with BAX to bind to the HSP60 protein

  • J Virol. 2025 Feb 27:e0140124. doi: 10.1128/jvi.01401-24.
Zhiyong Xiang  1  2 ,  Zhen Xu  1  2 ,  Wenlian Weng  1  2 ,  Hua Wang  1  2 ,  Jiajun Wu  3 ,  Fei Jiang  3 ,  Yajin Qu  1  2 ,  Quanlin Li  1  2 ,  Peng Gao  1  2 ,  Lei Zhou  1  2 ,  Xinna Ge  1  2 ,  Xin Guo  1  2 ,  Jun Han  1  2 ,  Yongning Zhang  1  2 ,  Hanchun Yang  1  2
Affiliations
  • 1. National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China.
  • 2. Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China.
  • 3. China Animal Disease Control Center, Beijing, China.
PMID: 40013993 DOI: 10.1128/jvi.01401-24
Abstract

Induction of cell Apoptosis is a critical pathogenic feature of the African swine fever virus (ASFV), a devastating threat to the world pig industry, but the underlying mechanisms have remained unclear. Here, we report the genome-wide screening and identification of 27 ASFV-encoded Apoptosis inducers. Of them, the viral protein MGF360-16R was found to be a mitochondria-targeting protein and exhibits strong activity to induce mitochondrial-dependent Apoptosis. Interestingly, this protein exhibits a dynamic distribution pattern during viral Infection of porcine macrophages; it is mainly localized to the viral factory in the early stage and then shifts a portion to mitochondria in the late stage, a timing that coincides with virus-induced Apoptosis. Mechanistically, MGF360-16R interacts with and competes for the cellular heat shock protein 60 (HSP60), and this results in the release of Bax from the HSP60-BAX complex, leading to the activation of Bax and induction of Apoptosis. The ASFV mutant lacking MGF360-16R showed a reduced ability to induce cellular Apoptosis, highlighting the complex nature of ASFV-induced cell Apoptosis. Overall, our study adds a new function to MGF360-16R and reveals a novel mechanism of ASFV-mediated cell Apoptosis.

Importance: ASFV is a complex virus with a huge genome and numerous encoded proteins. Induction of cell Apoptosis is associated with pathological damage in pigs caused by ASFV, but its inducers and underlying mechanisms remain unclear. Through genome-wide screening, the viral protein MGF360-16R was identified as a potent Apoptosis Inducer with a unique localization transfer from the viral factory to mitochondria during ASFV Infection of porcine macrophages. MGF360-16R induces Apoptosis by interacting with the cellular HSP60 protein to release Bax from the HSP60-BAX complex in a competitive binding manner. Our research findings not only reveal a novel function of MGF360-16R but also provide clues for understanding the pathogenesis of ASFV and potentially developing new therapeutic strategies.

Keywords
African swine fever virus (ASFV); BAX; HSP60; MGF360-16R; apoptosis; porcine macrophages.
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