Annexin A2 extracellular translocation and virus interaction: A potential target for antivirus‐drug discovery

The endoplasmic reticulum (ER) plays an essential role in Ca2+ concentration balance and protein biosynthesis. During infection, the virus needs to complete its life process with the help of ER. At the same time, ER also produces ER stress (ERS), which induces apoptosis to resist virus infection. Our study explored the Ca2+ concentration, ERS, and the apoptosis mechanism after porcine circovirus 2 (PCV2) infection. We show here that PCV2 infection induces the increased cytoplasmic Ca2+ level and PK-15 cell ER swelling. The colocalization of phospholipase C (PLC) and inositol 1,4,5-trisphosphate receptor (IP3R) in the cytoplasm was observed by laser confocal microscopy. Western blot and quantitative polymerase chain reaction experiments confirmed that PLC and IP3R expression levels increased after PCV2 infection, and Ca2+ concentration in the cytoplasm increased after virus infection. These results suggest that PCV2 infection triggers ERS of PK-15 cells via the PLC–IP3R–Ca2+ signaling pathway to promote the release of intracellular Ca2+ and led to cell apoptosis.

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“…Increasing the concentration of Ca 2+ in the cytoplasm can enhance virus release (Aliyu et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…As mentioned in previous reports, Ca 2+ is a limiting cytokine for virus budding. Increasing the concentration of Ca 2+ in the cytoplasm can enhance virus release ( Aliyu et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

PCV2 Triggers PK-15 Cell Apoptosis Through the PLC–IP3R–Ca2+ Signaling Pathway

Wang

Sun

et al. 2021

Front. Microbiol.

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“…This further stressed the potential of targeting filopodia and its machineries in the control of this virus. This was reviewed extensively by Aliyu, et al 82 …”

Section: Viral Interaction and Motility On Filopodia Enhances Infectionmentioning

confidence: 99%

Proteomes, kinases and signalling pathways in virus‐induced filopodia, as potential antiviral therapeutics targets

Aliyu

Kumurya

Bala

et al. 2020

Reviews in Medical Virology

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Summary Filopodia are thin finger‐like protrusions at the surface of cells that are internally occupied with bundles of tightly parallel actin filaments. They play significant roles in cellular physiological processes, such as adhesion to extracellular matrix, guidance towards chemo‐attractants and in wound healing. Filopodia were recently reported to play important roles in viral infection including initial viral attachment to host cells, cell surfing, viral trafficking, internalization, budding, virus release and spread to other cells in a form that would avoid the host immune system. The detailed virus‐host protein interactions underlying most of these processes remain to be elucidated. This review will describe some reported virus‐host protein interactions on filopodia with the aim of identifying potential new anti‐virus therapeutic targets. Exploring this research area may lead to the development of novel classes of anti‐viral therapeutics that can block signalling pathways used by the virus to trigger filopodia formation. Successful compounds would inhibit initial virus attachment, formation of filopodia, expression of putative virus binding protein, extracellular virus trafficking, and budding.

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“…Annexin A2 (ANXA2, also known as calpactin I or lipocortin II) is a multifunctional protein that can reversibly bind to phospholipid membranes and calcium ions (Ca 2+ ) [17]. ANXA2 belongs to the membrane scaffold and binding protein, and is mainly expressed in the plasma membrane and intracellular vesicles [18,19]. Although ANXA2 exists in the cytoplasm as a monomer, it generally exists as a heterotetrameric complex composed of S100A10 dimer and two ANXA2 molecules [20,21].…”

Section: Introductionmentioning

confidence: 99%

ANXA2 enhances virus replication through negatively regulating cGAS-STING and RLRs-mediated signal pathway

Huang

Xue

et al. 2021

Preprint

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Host nucleic acid receptors can recognize the viral DNA or RNA upon virus infection, which further triggers multiple signal pathways to promote the translocation of the interferon regulatory factor 3 (IRF3) into nucleus and produce type I interferon (IFN), leading to the host antiviral response. Here, we report a novel negative regulator Annexin A2 (ANXA2) that regulates type I IFN production through multiple mechanisms. Ectopic expression of ANXA2 inhibited the production of type I IFN induced by DNA- and RNA viruses and enhanced virus replication, while knockout of ANXA2 expression enhanced the production of type I IFN and inhibited virus replication. Mechanistically, ANXA2 not only disrupted MDA5 recruiting MAVS, but also inhibited the interaction between MAVS and TRAF3 upon RNA virus infection. In addition, ANXA2 impacted the translocation of STING from endoplasmic reticulum to Golgi apparatus upon DNA virus infection. Interestingly, ANXA2 also inhibited IRF3 phosphorylation and nuclear translocation through competing with TANK-binds kinase 1 (TBK1) and inhibitor-κB kinase ε (IKKε) for binding to IRF3. Anxa2 deficiency in vivo increased the production of type I IFN, which resulted in suppression of encephalomyocarditis virus (EMCV) replication. Our findings reveal that ANXA2, as a negative regulator of type I IFN production, plays an important role in regulating the host antiviral responses.Author summaryAnnexin is a family of evolutionarily conserved multi-gene proteins, which are widely distributed in various tissues and cells of plants and animals. These proteins can reversibly bind to phospholipid membranes and to calcium ions (Ca2+). To date, several studies have confirmed that some members of the Annexin family regulate the antiviral innate immune response. Until now, regulation of the production of type I IFN by ANXA2 is not reported. In this study, ANXA2 were found to strongly inhibit the production of type I IFN, leading to increased virus replication while knockout of ANXA2 expression inhibited virus replication by increasing the amount of IFN. Compared with wild-type littermates, ANXA2 deficiency mice produced more type I IFN to inhibit virus replication. Our results provide methanistic insights into the novel role of ANXA2 in the antiviral innate immune responses.

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Annexin A2 extracellular translocation and virus interaction: A potential target for antivirus‐drug discovery

Cited by 23 publications

References 84 publications

PCV2 Triggers PK-15 Cell Apoptosis Through the PLC–IP3R–Ca2+ Signaling Pathway

PCV2 Triggers PK-15 Cell Apoptosis Through the PLC–IP3R–Ca2+ Signaling Pathway

Proteomes, kinases and signalling pathways in virus‐induced filopodia, as potential antiviral therapeutics targets

ANXA2 enhances virus replication through negatively regulating cGAS-STING and RLRs-mediated signal pathway

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