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

Abstract

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.