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

Transmissible gastroenteritis virus (TGEV) infection can down-regulate circBIRC6-2 expression and induce mitochondrial permeability transition pore (mPTP) opening abnormally. BIRC6-236aa, encoded by circBIRC6-2, can suppress mPTP opening by interacting with VDAC1. However, the molecular mechanism of circBIRC6-2 downregulation by TGEV infection is unsuspected, and it is unclear that whether BIRC6-236aa can inhibit mPTP opening by post translational modifications (PTM) and downstream regulatory proteins. In this study, we found that TGEV membrane protein (TGEV-M) can suppress circBIRC6-2 expression by interacting with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) and inhibiting the translocation of hnRNPA1, which can bind to baculoviral IAP repeat containing 6 (birc6) pre-mRNA to promote the formation of circBIRC6-2. In addition, glycogen synthase kinase-3 beta (GSK-3β) can phosphorylate Ser180 of BIRC6-236aa, and phosphorylated-BIRC6-236aa (p-BIRC6-236aa) can inhibit mPTP opening. 271 differential expression proteins (DEPs) were identified after overexpression of BIRC6-236aa. ATP synthase, H transporting, mitochondrial F1 complex, delta subunit (ATP5D, also named ATP5F1D), one of the DEPs was down-regulated in response to BIRC6-236aa, and ATP5D can promote mPTP opening induced by TGEV. In conclusion, TGEV-M can suppress the expression of circBIRC6-2 through targeting hnRNPA1. The Ser180 of BIRC6-236aa encoded by circBIRC6-2 can be phosphorylated by GSK-3β, and p-BIRC6-236aa can inhibit mPTP opening by down-regulating ATP5D expression.