Circular RNA CircEZH2 Suppresses Transmissible Gastroenteritis Coronavirus-induced Opening of Mitochondrial Permeability Transition Pore via Targeting MiR-22 in IPEC-J2

Abstract

Transmissible gastroenteritis (TGE) is a contagious and infectious disease that is characterized by severe vomiting and diarrhea of swine , especially piglet, and caused by transmissible gastroenteritis coronavirus (TGEV) . TGEV infection provokes mitochondrial damage of porcine intestinal epthelial cell (IPEC), which is responsible for inflammation and cell death. In our previous study, we have demonstrated that circular RNA circEZH2 was down-regulated during TGEV infection and promoted the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) via targeting miR-22 in porcine intestinal epithelial cell line (IPEC-J2). Activation of NF-κB is an important factor for mitochondrial damage. Mitochondrial permeability transition pore (mPTP) opening is a key reason for mitochondrial damage. So, we speculate that circEZH2 may regulate TGEV-induced mPTP opening via NF-kB pathway. In the present study, we found that mPTP opening of IPEC-J2 was occured during TGEV infection and suppressed by circEZH2 via attaching miR-22. Hexokinase 2 (HK2) and interleukin 6 (IL-6) were identified as the targets of miR-22. Silencing HK2 enhanced TGEV-induced mPTP opening, while no effect on NF-κB pathway. Silencing IL-6 promoted TGEV-induced mPTP opening and inhibited NF-κB pathway. Inhibitor of NF-κB increased TGEV-induced mPTP opening. The data revealed that TGEV-induced mPTP opening was regulated via two pathways: circEZH2/miR-22/HK2 axis and circEZH2/miR-22/IL-6/NF-κB axis.

The emerging role and significance of circular RNAs in viral infections and antiviral immune responses: possible implication as theranostic agents

“…By activating NF-κB pathway, IL-6 inhibited mPTP opening, while HK2 had no significant impact on the activation of NF-κB pathway. The authors concluded that two pathways including circEZH2/miR-22/ IL-6/NF-κB axis and circEZH2/miR-22/HK2 axis are involved in regulating TGEV-induced mPTP opening [57].…”

The effect of mitochondrial transplantation therapy from different gender on inhibiting cell proliferation of malignant melanoma

“…Retrograde transcriptional signaling of mitochondria plays vital role as stress sensors to adapt its environment 25 . The retrograde signals between mitochondria and nucleus, including ATP, ROS, UPR mt , 2-hydroxyglutarate, opening of mitochondrial permeability transition pore, can regulate gene expression in the nucleus 26 , 27 . Recently, a potential link between mitochondrial stress and widespread changes in chromatin structure has been proposed 28 .…”

The role of circular RNAs in viral infection and related diseases

“…Overexpression of circEZH2 in IPEC-J2 cells inhibited TGEV-induced mitochondrial permeability transition pore (mPTP) opening via attaching miR-22 to regulate hexokinase 2 (HK2) and interleukin 6 (IL-6), while silencing of IL-6 supressed activation of NF-κB pathway. This study provides potential drug targets for the prevention and treatment of TGE ( Zhao et al, 2019b ). Studies have also examined circRNA expression profiles by using high-throughput sequencing in MBDK cells infected with bovine viral diarrhea virus (BVDV) ( Li et al, 2019 ) and in the silkworm following bombyx mori nuclear polyhedrosis virus (BmNPV) infection ( Hu et al, 2018 ).…”

“… CircRNA Effect on virus Regulated pathway Refer-ence circ_0000479 Overexpression promotes the expression of RIG-I and hampering HTNV replication circ_0000479/ miR-149-5p/ RIG-I pathway ( Lu et al, 2020 ) hsa_circ_0004812 Knockdown expression promotes the IFN-α/β, and inhibits HBV replication. circ_0004812/ miR-1287-5p/ FSTL1 axis to regulate IFN-induced immune response ( Zhang and Wang, 2020 ) circRNA_100338 Overexpression enhanced migratory and invasive ability of cancer cells circRNA_100338 / miR-1413p axis to regulate invasive potential in liver cancer cells ( Huang et al, 2017 ) circ-GATAD2A Knockdown expression enhances autophagy and inhibits IAV H1N1 replication, reverse after overexpression circ-GATAD2A/ VPS34-dependent autophagy pathway ( Yu et al, 2019 ) circ-Vav3 Overexpression induces EMT, promote ALV-J related tumorigenesis circ-Vav3/gga-miR-375/YAP1 axis induces EMT pathway ( Zhang et al, 2019 ) circEZH2 Overexpression inhibits TGEV-induced mPTP opening and regulate NF-κB activation circEZH2/ miR-22/ HK2 axis, circEZH2 /miR-22/IL-6/ NF-Kb pathway to regulate mPTP opening ( Zhao et al, 2019b ) …”

“…Studies have shown that the virus-generated circRNAs or differentially expressed host circRNAs can be used as candidate biomarkers for viral infection ( Wang et al, 2018 ; Yu et al, 2020 ; Zhao et al, 2019a ). Meanwhile, circRNAs are involved in regulating antiviral immune response ( Chen et al, 2017 ; Li et al, 2017 ), viral replication ( Lu et al, 2020 ; Sekiba et al, 2018 ; Tagawa et al, 2018 ; Yu et al, 2019 ; Zhang and Wang, 2020 ), and pathogenesis of infectious diseases ( Zhang et al, 2019 ; Zhao et al, 2019a , b ). In this review, we summarized the current understanding of circRNAs, mainly focused on the circRNAs in the regulation of viral infections.…”