P58^IPKinhibits coxsackievirus-induced apoptosis via the PI3K/Akt pathway requiring activation of ATF6a and subsequent upregulation of mitofusin 2

Abstract

Summary Previously we found that prolonged endoplasmic reticulum (ER) stress caused by coxsackievirus B3 (CVB3) infection led to p58IPK downregulation and subsequent cell apoptosis. This finding implies that p58 IPK expression benefits cell survival and counteracts CVB3-induced apoptosis. In testing this hypothesis, we first found that PI3K/Akt survival pathway is more sensitive than ERK1/2 in response to p58 IPK expression. This finding was further verified by silencing p58 IPK with specific siRNAs, which led to the significant suppression of phosphorylation of Akt (p-Akt) but not ERK1/2. Further, using CVB3-infected cell line expressing dominant negative ATF6a (DN-ATF6a), we found that expression of p58 IPK and p-Akt was significantly reduced, which led to the decreased cell viability. However, when the DN-ATF6a cells were transiently transfected with p58 IPK , an opposite result was obtained. Finally, by CVB3 infection of cells stably expressing p58 IPK , we found that CVB3-induced mitochondriamediated apoptosis was suppressed, which was evidenced by the reduced cytochrome c release and upregulation of the mitochondrial membrane protein mitofusin 2. However, silencing p58 IPK with either specific siRNAs or DN-ATF6a sensitized cells to CVB3-induced apoptosis. These results suggest that p58 IPK suppresses CVB3-induced apoptosis through selective activation of PI3K/Akt pathway that requires activation of ATF6a and subsequently upregulates mitofusin 2.

Mitofusin 2 Promotes Apoptosis of CD4+ T Cells by Inhibiting Autophagy in Sepsis

“…So LV-Mfn2 RNAi lentiviral vectors were also constructed and used to transfect Jurkat T cells to downregulate Mfn2 expression in the present study. In the current study, both overexpression of Mfn2 and silencing of Mfn2 resulted in significantly increased cell apoptosis, which was consistent with findings from previous studies [ 8 , 9 , 11 , 45 , 46 ]. These data imply that a balance of Mfn2 expression maintains cellular homeostasis, whereas an imbalance leads to cell apoptosis.…”

Therapeutic Potential of Oxytocin in Atherosclerotic Cardiovascular Disease: Mechanisms and Signaling Pathways

“…(1) OT can increase cardiac expression of connexin 43 (Gassanov et al, 2008; Kim et al, 2012), which was known to inhibit GSK-3β signaling in cardiomyocytes (Ishikawa et al, 2012). (2) OT can activate PI3K/Akt pathway (Gonzalez-Reyes et al, 2015) that is known to exert antiapoptosis in association with upregulation of mitofusin 2 (Zhang et al, 2014). (3) By activating AMPK, OT can decrease the Ca 2+ oscillation through increasing mitofusin 2 expression (Wang F. et al, 2015) and suppressing GSK-3β by activation of insulin receptor (Chopra et al, 2012) that was known to increase mitofusin 2 and decrease GSK-3β (Litwiniuk et al, 2016).…”

Mitofusin 2 Exerts a Protective Role in Ischemia Reperfusion Injury Through Increasing Autophagy

“…Mfn2 played a role in maintaining mitochondrial function under stress [16]. Furthermore, it also modulated cellular processes through several molecular pathways, like PI3K/Akt, Bcl-2/Bax, and antiviral signaling [17-19]. Recently, it was reported that mitochondria supply membranes for autophagosome biogenesis during starvation and that Mfn2 was crucial for this processs [20].…”