Highly Pathogenic H5N1 Avian Influenza Virus Induces Extracellular Ca
            <sup>2+</sup>
            Influx, Leading to Apoptosis in Avian Cells

Ueda, Mayo; Daidoji, Tomo; Du, Anariwa; Yang, Cheng-Song; Ibrahim, Madiha S.; Ikuta, Kazuyoshi; Nakaya, Takaaki

doi:10.1128/jvi.01923-09

Cited by 55 publications

(50 citation statements)

References 64 publications

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“…Although the precise mechanism by which IAVs induce [Ca 2 þ ]i elevation remains obscure, the elimination of Ca 2 þ signalling by BAPTA-AM resulted in almost complete inhibition of virus internalization. In addition to this central role of Ca 2 þ in IAV infection, Ca 2 þ is also implicated in apoptosis of cells infected by a highly pathogenic H5N1 virus 50 , suggesting that the development of agents that target Ca 2 þ signalling might provide a new approach to the prevention and treatment of infection with a variety of influenza subtypes.…”

Section: Discussionmentioning

confidence: 99%

A Ca2+-dependent signalling circuit regulates influenza A virus internalization and infection

et al. 2013

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Various viruses enter host cells via endocytosis, but the molecular mechanisms underlying the specific internalization pathways remain unclear. Here we show that influenza A viruses (IAVs) enter cells via redundant pathways of clathrin-mediated and clathrin-independent endocytosis, with intracellular Ca2+ having a central role in regulation of both pathways by activating a signalling axis comprising RhoA, Rho-kinase, phosphatidylinositol 4-phosphate 5-kinase (PIP5K) and phospholipase C (PLC). IAV infection induces oscillations in the cytosolic Ca2+ concentration of host cells, the prevention of which markedly attenuates virus internalization and infection. The small GTPase RhoA is found both to function downstream of the virus-induced Ca2+ response and itself to induce Ca2+ oscillations in a manner dependent on Rho-kinase and subsequent PIP5K-PLC signalling. This signalling circuit regulates both clathrin-mediated and clathrin-independent endocytosis during virus infection and seems to constitute a key mechanism for regulation of IAV internalization and infection

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Section: Discussionmentioning

confidence: 99%

A Ca2+-dependent signalling circuit regulates influenza A virus internalization and infection

et al. 2013

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“…However, when [Ca 2ϩ ] i increases, stimulated AnxA6 is targeted to distinct subcellular membrane locations, such as the plasma membrane, endosomes, or secretory vesicles. Thus, cytosolic AnxA6 is probably translocated to distinct subcellular membrane locations upon virus infection, due to the dysregulation of Ca 2ϩ homeostasis observed after IAV infection (24,58). If AnxA6 is overexpressed and targeted at the plasma membrane, it has been shown that it interacts with, recruits, and causes the rearrangement of F-actin, resulting in stabilization of the cortical cytoskeleton (40).…”

Section: Discussionmentioning

confidence: 99%

Human Annexin A6 Interacts with Influenza A Virus Protein M2 and Negatively Modulates Infection

Kien

Manière

et al. 2012

J Virol

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The influenza A virus M2 ion channel protein has the longest cytoplasmic tail (CT) among the three viral envelope proteins and is well conserved between different viral strains. It is accessible to the host cellular machinery after fusion with the endosomal membrane and during the trafficking, assembly, and budding processes. We hypothesized that identification of host cellular interactants of M2 CT could help us to better understand the molecular mechanisms regulating the M2-dependent stages of the virus life cycle. Using yeast two-hybrid screening with M2 CT as bait, a novel interaction with the human annexin A6 (AnxA6) protein was identified, and their physical interaction was confirmed by coimmunoprecipitation assay and a colocalization study of virus-infected human cells. We found that small interfering RNA (siRNA)-mediated knockdown of AnxA6 expression significantly increased virus production, while its overexpression could reduce the titer of virus progeny, suggesting a negative regulatory role for AnxA6 during influenza A virus infection. Further characterization revealed that AnxA6 depletion or overexpression had no effect on the early stages of the virus life cycle or on viral RNA replication but impaired the release of progeny virus, as suggested by delayed or defective budding events observed at the plasma membrane of virus-infected cells by transmission electron microscopy. Collectively, this work identifies AnxA6 as a novel cellular regulator that targets and impairs the virus budding and release stages of the influenza A virus life cycle. Influenza A virus (IAV) is an enveloped virus with a segmented negative-sense RNA genome. The eight RNA segments encode 11 proteins (44). Influenza virus is pleomorphic (23), forming spherical virions that are ϳ100 nm in diameter as well as filamentous virions that are ϳ100 nm in diameter and over 20 m in length. The viral lipid envelope, derived by budding from the apical plasma membrane of the host cell, contains two major envelope glycoproteins, the receptor-binding/membrane fusion protein hemagglutinin (HA) and the enzyme neuraminidase (NA). A third minor (ϳ16 to 20 molecules/virion) integral membrane protein, M2, is a proton-selective ion channel that allows virion interior acidification for efficient uncoating after fusion in endosomes. M2 contains 97 amino acid residues and assembles into a homotetramer. This small type III integral membrane protein contains a single 19-residue transmembrane domain that forms the pore of the ion channel, a short (24-residue) amino-terminal ectodomain, and a long (54-residue) carboxy-terminal cytoplasmic domain (27,34,45). This cytoplasmic tail (CT) is highly conserved among viral strains (57).In the early stages of the replication cycle, after virus internalization by endocytosis, endosomal acidification activates M2 ion channel activity, causing acidification of the virus interior and leading to dissociation of the matrix protein M1 from the viral ribonucleoprotein (vRNP) complex (reviewed in reference 47). M2 is the targ...

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“…However, upon apoptosis induction, nuclear translocation of AIFM1 occurs via a caspaseindependent pathway. This pathway has recently been shown to be activated by influenza virus (H5N1), leading to mitochondrial dysfunction and cell death through the induction of an extracellular Ca2 ϩ influx (62). However, the viral component involved in the activation of this caspase-independent pathway is unknown.…”

Section: Vol 85 2011mentioning

confidence: 99%

Comprehensive Proteomic Analysis of Influenza Virus Polymerase Complex Reveals a Novel Association with Mitochondrial Proteins and RNA Polymerase Accessory Factors

Bradel-Tretheway

Mattiacio

Krasnoselsky

et al. 2011

J Virol

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The trimeric RNA polymerase complex (3P, for PA-PB1-PB2) of influenza A virus (IAV) is an important viral determinant of pathogenicity and host range restriction. Specific interactions of the polymerase complex with host proteins may be determining factors in both of these characteristics and play important roles in the viral life cycle. To investigate this question, we performed a comprehensive proteomic analysis of human host proteins associated with the polymerase of the well-characterized H5N1 Vietnam/1203/04 isolate. We identified over 400 proteins by liquid chromatography-tandem mass spectrometry (LC-MS/MS), of which over 300 were found to bind to the PA subunit alone. The most intriguing and novel finding was the large number of mitochondrial proteins (ϳ20%) that associated with the PA subunit. These proteins mediate molecular transport across the mitochondrial membrane or regulate membrane potential and may in concert with the identified mitochondrion-associated apoptosis inducing factor (AIFM1) have roles in the induction of apoptosis upon association with PA. Additionally, we identified host factors that associated with the PA-PB1 (68 proteins) and/or the 3P complex (34 proteins) including proteins that have roles in innate antiviral signaling (e.g., ZAPS or HaxI) or are cellular RNA polymerase accessory factors (e.g., polymerase I transcript release factor [PTRF] or Supt5H). IAV strain-specific host factor binding to the polymerase was not observed in our analysis. Overall, this study has shed light into the complex contributions of the IAV polymerase to host cell pathogenicity and allows for direct investigations into the biological significance of these newly described interactions.The trimeric RNA (3P) influenza virus polymerase complex (PA-PB1-PB2) assembles in the nucleus, where influenza virus replication occurs. Several events inside the host cell must take place in order to support viral replication, such as the regulation of early antiviral host responses, host protein shutoff, and nuclear transport of viral RNA and proteins (21,29,63). These events require the viral RNA polymerase to interact with cellular factors, some of which may also be important for host range specificity but have yet to be identified (17,44). A range of RNA interference (RNAi)-based, genome-wide screens have been published recently that identified host factors involved in influenza virus replication (4,22,31,35,52,56). Although the degree of overlap between these studies was minimal, similar biological pathways and functional classifications were identified, suggesting their importance in the influenza virus infectious cycle. Watanabe et al. (67) compiled a list of 128 proteins that affected influenza virus replication in at least two out of the six screens. These included proteins involved in the nuclear import of viral ribonucleoproteins (vRNPs), such as importin family members and nuclear pore complex proteins.Other studies have attempted to directly identify proteins that interact with either the influenza virus po...

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Highly Pathogenic H5N1 Avian Influenza Virus Induces Extracellular Ca ²⁺ Influx, Leading to Apoptosis in Avian Cells

Cited by 55 publications

References 64 publications

A Ca2+-dependent signalling circuit regulates influenza A virus internalization and infection

A Ca2+-dependent signalling circuit regulates influenza A virus internalization and infection

Human Annexin A6 Interacts with Influenza A Virus Protein M2 and Negatively Modulates Infection

Comprehensive Proteomic Analysis of Influenza Virus Polymerase Complex Reveals a Novel Association with Mitochondrial Proteins and RNA Polymerase Accessory Factors

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Highly Pathogenic H5N1 Avian Influenza Virus Induces Extracellular Ca 2+ Influx, Leading to Apoptosis in Avian Cells

Cited by 55 publications

References 64 publications

A Ca2+-dependent signalling circuit regulates influenza A virus internalization and infection

A Ca2+-dependent signalling circuit regulates influenza A virus internalization and infection

Human Annexin A6 Interacts with Influenza A Virus Protein M2 and Negatively Modulates Infection

Comprehensive Proteomic Analysis of Influenza Virus Polymerase Complex Reveals a Novel Association with Mitochondrial Proteins and RNA Polymerase Accessory Factors

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Highly Pathogenic H5N1 Avian Influenza Virus Induces Extracellular Ca ²⁺ Influx, Leading to Apoptosis in Avian Cells