Influenza A virus use of BinCARD1 to facilitate the binding of viral NP to importin α7 is counteracted by TBK1-p62 axis-mediated autophagy

Abstract

As a major component of the viral ribonucleoprotein (vRNP) complex in influenza A virus (IAV), nucleoprotein (NP) interacts with isoforms of importin α family members, leading to the import of itself and vRNP complex into the nucleus, a process pivotal in the replication cycle of IAV. In this study, we found that BinCARD1, an isoform of Bcl10-interacting protein with CARD (BinCARD), was leveraged by IAV for efficient viral replication. BinCARD1 promoted the nuclear import of the vRNP complex and newly synthesized NP and thus enhanced vRNP complex activity. Moreover, we found that BinCARD1 interacted with NP to promote NP binding to importin α7, an adaptor in the host nuclear import pathway. However, we also found that BinCARD1 promoted RIG-I-mediated innate immune signaling by mediating Lys63-linked polyubiquitination of TRAF3, and that TBK1 appeared to degrade BinCARD1. We showed that BinCARD1 was polyubiquitinated at residue K103 through a Lys63 linkage, which was recognized by the TBK1-p62 axis for autophagic degradation. Overall, our data demonstrate that IAV leverages BinCARD1 as an important host factor that promotes viral replication, and two mechanisms in the host defense system are triggered—innate immune signaling and autophagic degradation—to mitigate the promoting effect of BinCARD1 on the life cycle of IAV.

Holistic Assessment Based On Hepatocyte Mitochondria: Lycopene Repairs Oxidized mtDNA to Alleviate Mitochondrial Stress Induced by Atrazine

“…35 PINK1 phosphorylates Parkin and transfers it to mitochondria, so Parkin protein is significantly altered in mitochondrial protein extracts. 34 Mitochondrial p62 is reduced by the depletion of mitophagy, which agrees with the results of the present study. 36 ATZ causes strong mitophagy, whereas LYC mitigates mitophagy to some extent and maintains mitochondrial homeostasis.…”

“…The accumulation of Parkin and PINK1 in mitochondria confirms the occurrence of mitophagy . PINK1 phosphorylates Parkin and transfers it to mitochondria, so Parkin protein is significantly altered in mitochondrial protein extracts . Mitochondrial p62 is reduced by the depletion of mitophagy, which agrees with the results of the present study .…”

“…P62 is the first receptor identified as a scavenger of protein polymers and damaged mitochondria. The p62 attached to the damaged mitochondria is ubiquitinated and attached to the autophagosome, so the p62 protein and mitochondria are rapidly cleared . Beclin1, Parkin, and PINK1 proteins increase and p62 proteins decrease in total proteins, while in the protein extracts of mitochondria, the fade of GAPDH represents its nearly cytoplasmic absence, and VDAC1 is used as an internal reference for mitochondrial proteins.…”

Advances in deciphering the interactions between viral proteins of influenza A virus and host cellular proteins

“…The interaction between the NLS of NP and isoforms of importin α family members further recruits importin β, which mediates the nuclear import of NP and the vRNP complex. During this process, Bcl10-interacting protein with CARD 1 (BinCARD1) binds to NP and specifically enhances the interaction between NP and importin α7, thus facilitating the nuclear import of the vRNP complex and newly synthesize NP ( Wang et al, 2022a ). In contrast, moloney leukemia virus 10 (MOV10) interacts with NP and disrupts the binding of NP to importin α, resulting in the retention of NP in the cytoplasm and the consequent impairment of the vRNP complex function ( Zhang et al., 2016 ).…”

ARIH1 inhibits influenza A virus replication and facilitates RIG-I dependent immune signaling by interacting with SQSTM1/p62

“…Influenza A virus is a single-strand negative-sense RNA virus contagious pathogen that is responsible for severe respiratory infection in humans and animals worldwide and has received attention in the current COVID-19 pandemic [ 3 , 8 ]. The virus also induces type I interferon production primarily through the activation of RIG-I pathway, during which multiple host factors are involved [ 1 , 9 – 12 ].…”