Nonstructural Protein NS1 of Influenza Virus Disrupts Mitochondrial Dynamics and Enhances Mitophagy via ULK1 and BNIP3

Abstract

Nonstructural protein 1 (NS1) of influenza virus (IFV) is essential for evading interferon (IFN)-mediated antiviral responses, thereby contributing to the pathogenesis of influenza. Mitophagy is a type of autophagy that selectively removes damaged mitochondria. The role of NS1 in IFV-mediated mitophagy is currently unknown. Herein, we showed that overexpression of NS1 protein led to enhancement of mitophagy. Mitophagy induction via carbonyl cyanide 3-chlorophenylhydrazone treatment in IFV-infected A549 cells led to increased viral replication efficiency, whereas the knockdown of PTEN-induced kinase 1 (PINK1) led to the opposite effect on viral replication. Overexpression of NS1 protein led to changes in mitochondrial dynamics, including depolarization of mitochondrial membrane potential. In contrast, infection with NS1-deficient virus resulted in impaired mitochondrial fragmentation, subsequent mitolysosomal formation, and mitophagy induction, suggesting an important role of NS1 in mitophagy. Meanwhile, NS1 protein increased the phosphorylation of Unc-51-like autophagy activating kinase 1 (ULK1) and the mitochondrial expression of BCL2- interacting protein 3 (BNIP3), both of which were found to be important for IFV-mediated mitophagy. Overall, these data highlight the importance of IFV NS1, ULK1, and BNIP3 during mitophagy activation.

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“…In contrast, Ru-IM-treated cells exhibit increased levels of fragmentation, indicative of dysfunctional mitochondria. 27 These results reflect interaction with the organelle, confirming preliminary findings in TNBC cell lines. 20 Thus, further studies were completed to assess the potential changes to mitochondrial function.…”

“…Zoomed images of the mitochondrial channel are shown in Figure C with DMSO-treated cells seeing standard tubular-shaped mitochondria. In contrast, Ru-IM-treated cells exhibit increased levels of fragmentation, indicative of dysfunctional mitochondria . These results reflect interaction with the organelle, confirming preliminary findings in TNBC cell lines .…”

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“…Not surprisingly, disrupting the MAPK1/3 kinases to increase the phosphorylation of ULK1 and inducing mitophagy, which works well in the treatment of bone metastases with low ULK1 levels 156 . Nonstructural protein 1 (NS1) protein could also trigger the phosphorylation of ULK1 and enhances the mitochondrial expression of BCL2-interacting protein 3, which were vital for influenza virus mediated mitophagy 157 .…”

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“…Accumulation of IAV in the mitochondria breaks the equilibrium of mitochondrial fusion and fission, causing their fragmentation (9) and leading to the leak of superoxide ion into the cytoplasm (10). Besides PB2, the nonstructural protein 1 (NS1) can also induce fragmentation of mitochondria by altering its dynamics (11), which indicates the stimulation role of NS1 in ROS…”