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TGEV-M up-regulates ATP5D to promote mPTP opening via inhibiting BIRC6-236aa encoded by circBIRC6-2

Jianxiong Guo1, Lingling Chang1, Fengxi Zhang1

  • 1College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, PR China.

Veterinary Microbiology
|June 21, 2025
PubMed

Insights

Transmissible gastroenteritis virus (TGEV) infection suppresses circBIRC6-2 expression via TGEV-M and hnRNPA1 interaction. Phosphorylated BIRC6-236aa inhibits mitochondrial pore opening by downregulating ATP5D.

Area of Science:

  • Virology
  • Molecular Biology
  • Mitochondrial Biology

Background:

  • Transmissible gastroenteritis virus (TGEV) infection causes abnormal mitochondrial permeability transition pore (mPTP) opening.
  • circBIRC6-2, encoding BIRC6-236aa, normally suppresses mPTP opening, but its downregulation by TGEV is poorly understood.

Purpose of the Study:

  • To elucidate the molecular mechanism of circBIRC6-2 downregulation by TGEV.
  • To investigate how BIRC6-236aa inhibits mPTP opening, including post-translational modifications and downstream targets.

Main Methods:

  • Investigated TGEV membrane protein (TGEV-M) interactions with hnRNPA1 and its role in circBIRC6-2 formation.
  • Analyzed the phosphorylation of BIRC6-236aa by GSK-3β and its effect on mPTP opening.
  • Utilized proteomic analysis to identify proteins differentially expressed upon BIRC6-236aa overexpression.

Main Results:

  • TGEV-M suppresses circBIRC6-2 expression by inhibiting hnRNPA1 translocation, which is crucial for circBIRC6-2 biogenesis.
  • Phosphorylation of BIRC6-236aa at Ser180 by GSK-3β generates p-BIRC6-236aa, which inhibits mPTP opening.
  • ATP5D, identified as a differentially expressed protein, promotes TGEV-induced mPTP opening and is downregulated by BIRC6-236aa.

Conclusions:

  • TGEV-M suppresses circBIRC6-2 expression by targeting hnRNPA1, disrupting circBIRC6-2 formation.
  • Phosphorylated BIRC6-236aa inhibits mPTP opening, partly by downregulating ATP5D expression.
  • This study reveals a novel mechanism by which TGEV manipulates host cell machinery to induce mitochondrial dysfunction.
Keywords:
ATP5DBIRC6-236aaHnRNPA1MPTPTGEV

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