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Graphical summary of annexin-microbe interactions. (1) Virus-associated annexins might (1a) help avoid the host innate immune response by modulating signaling pathways of PAMP-activated receptors (AnxA1/FPR; AnxA5/Stat1), (1b) act as facilitators required for efficient entry, or (1c) serve as ligands/receptors for binding to the cell surface. Intracellularly, annexins might assist in viral replication/assembly at (2a) (specialized) endomembranes or at (2b) the plasma membrane; and/or (3) affect virus budding, leading eventually to incorporation. F-actin binding annexins such as AnxA2 and AnxA8 might help organize membrane platforms for F-actin rearrangements in (4a) EPEC/EHEC and (4b) Salmonella infection. Microbe-host cell interaction might (5a) depend on annexin-assisted cellular processes (AnxA1/syncytium formation; AnxA6/endomembrane cholesterol balance and 5b) even affect annexin gene expression levels and post-translational modifications, leading to functional switches (relocalization, recruitment of binding partners) and externalization, as might be required for steps 1b, 1c, 2, 3.
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Emerging infectious diseases and drug-resistant infectious agents call for the development of innovative antimicrobial strategies. With pathogenicity now considered to arise from the complex and bi-directional interplay between a microbe and the host, host cell factor targeting has emerged as a promising approach that might overcome the limitations...
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... into virus particles has been observed and reported for several annexins (Figure 1, 1a-c). Proteomic analysis, for example, revealed that purified influenza A virus (IAV) particles contain annexins A1, A2, A4, A5, and A11 ( Shaw et al., 2008). ...
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... pathogens, mainly viruses, have been reported to utilize host cell surface associated annexins as receptors for cell binding and entry (Figure 1, 1b-c). The heterote- trameric complex formed by AnxA2 and its interaction partner S100A10 (formerly known as p11, belongs to the S100 protein family of Ca 2+ binding proteins) was proposed to contribute to the internalization of the most common high-risk human papillomavirus genotype, HPV16, which causes benign and malignant tumors of the mucosal and cutaneous epithelium. ...
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... this was not confirmed in another study (Pietropaolo and Compton, 1999). AnxA2 on the host cell surface was also implicated in the entry of enter- ovirus type 71 (EV71), the causative agent of the hand, foot, and mouth disease, to the host cell surface, possibly by binding the viral capsid protein VP1 on the cell surface (Yang et al., 2011). Rabbit vesivirus (RaV) virions might also depend on interaction with AnxA2 for their attach- ment and internalization ( González-Reyes et al., 2009). ...
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... viruses and bacteria exploit the host cell membrane systems to survive and replicate intracellularly, and they might need additional help from annexins (Figure 1, 2-5). AnxA1 was identified to Ca 2+ -dependently interact with fusogenic reptilian reovirus p14 and measles virus F and H proteins. ...
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... cells overexpressing AnxA6, IAV particles budding from the host cell plasma membrane are equipped with an envelope that is strongly reduced in cholesterol and exhibit severely impaired infectivity ( Musiol et al., 2013). A second study also observed defec- tive budding in AnxA6-overexpressing cells and identified AnxA6 as host cell factor that interacts with a proton- selective ion channel incorporated in the viral envelope, the M2 protein (Ma et al., 2012). The lowered late endoso- mal pH causes the M2 proton channel to conduct protons, leading to acidification of the viral interior and subse- quent release of viral ribonucleoprotein from the virus envelope ( Pielak and Chou, 2011). ...
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... from viruses, several pathogenic bacteria were postulated to interact with AnxA2 at certain stages of their life cycle (Figure 1, 4a,b). Due to its ability to bind actin and membranes, AnxA2 is one of the key players linking actin dynamics and membrane platforms in mammalian cells. ...
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... changes might be beneficial for the pathogen (such as enhanced or depressed host cell proliferation, or impaired immune response) or reflect the global cell response to the pathogenic attack. The following section concentrates on changes of annexin expression patterns and/or posttranscriptionally modi- fied annexins in infected cells that correlate directly with pathogen success (Figure 1, 5). However, whether the dif- ferent annexin expression levels reflect the pathogen's specific attempt to deregulate certain cellular processes or the host cell's efforts to fight the pathogenic attack is mostly unclear. ...
Citations
... Here, we highlight a few select examples of annexins in the host's response to pathogens that share a common functional theme. For a more comprehensive overview, we refer to a focused review of this topic 109 . ...
Annexins are cytosolic proteins with conserved three-dimensional structures that bind acidic phospholipids in cellular membranes at elevated Ca ²⁺ levels. Through this they act as Ca ²⁺ -regulated membrane binding modules that organize membrane lipids, facilitating cellular membrane transport but also displaying extracellular activities. Recent discoveries highlight annexins as sensors and regulators of cellular and organismal stress, controlling inflammatory reactions in mammals, environmental stress in plants, and cellular responses to plasma membrane rupture. Here, we describe the role of annexins as Ca ²⁺ -regulated membrane binding modules that sense and respond to cellular stress and share our view on future research directions in the field.
... Mouse models lacking individual members of the annexin gene family have been established and unravelled some of their in vivo functions. There are many excellent reviews on the annexin family covering the common and specific characteristics of individual annexin family members [1][2][3][4][5][6][7][8][9][10][11][12][13]. Hence, in the following, we provide only a brief overview necessary to appreciate the generation and functional implications from the in vivo analysis of the annexin mouse models. ...
... These processes are thought to control basic cellular functions that are pivotal to the regulation of growth, development, programmed cell death, but also cell motility, membrane repair and inflammatory response [1][2][3][4][5][6][7][8][9][10][11][12][13]. Ectopic overexpression or siRNA-mediated knockdown delivered great insights in the annexin biochemistry and broadened our knowledge substantially. ...
... These processes are thought to control basic cellular functions that are pivotal to the regulation of growth, development, programmed cell death, but also cell motility, membrane repair and inflammatory response [1][2][3][4][5][6][7][8][9][10][11][12][13]. Ectopic overexpression or siRNAmediated knockdown delivered great insights in the annexin biochemistry and broadened our knowledge substantially. ...
Routine manipulation of the mouse genome has become a landmark in biomedical research. Traits that are only associated with advanced developmental stages can now be investigated within a living organism, and the in vivo analysis of corresponding phenotypes and functions advances the translation into the clinical setting. The annexins, a family of closely related calcium (Ca²⁺)- and lipid-binding proteins, are found at various intra- and extracellular locations, and interact with a broad range of membrane lipids and proteins. Their impacts on cellular functions has been extensively assessed in vitro, yet annexin-deficient mouse models generally develop normally and do not display obvious phenotypes. Only in recent years, studies examining genetically modified annexin mouse models which were exposed to stress conditions mimicking human disease often revealed striking phenotypes. This review is the first comprehensive overview of annexin-related research using animal models and their exciting future use for relevant issues in biology and experimental medicine.
... Nevertheless, autophagy and autophagic cell death is essential in influenza replication and pathogenesis. In addition, annexin-pathogen interactions have been well elaborated recently and show that IAV utilize ANXA1 to regulate the host innate immune responses [21,36]. We recently showed that ANXA1 enhances influenza virus infection and viral replication by enhancing cell death and apoptosis [21]. ...
Influenza viruses have been shown to use autophagy for their survival. However, the proteins and mechanisms involved in the autophagic process triggered by the influenza virus are unclear. Annexin-A1 (ANXA1) is an immunomodulatory protein involved in the regulation of the immune response and Influenza A virus (IAV) replication. In this study, using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 (CRISPR associated protein 9) deletion of ANXA1, combined with the next-generation sequencing, we systematically analyzed the critical role of ANXA1 in IAV infection as well as the detailed processes governing IAV infection, such as macroautophagy. A number of differentially expressed genes were uniquely expressed in influenza A virus-infected A549 parental cells and A549 ∆ANXA1 cells, which were enriched in the immune system and infection-related pathways. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed the role of ANXA1 in autophagy. To validate this, the effect of mechanistic target of rapamycin (mTOR) inhibitors, starvation and influenza infection on autophagy was determined, and our results demonstrate that ANXA1 enhances autophagy induced by conventional autophagy inducers and influenza virus. These results will help us to understand the underlying mechanisms of IAV infection and provide a potential therapeutic target for restricting influenza viral replication and infection.
... The p11/AnxA2 heterotetramer also stimulates capsid uncoating and prevents lysosomal degradation of HPV16. A detailed review on the role of the p11/AnxA2 heterotetramer for the entry and trafficking of HPV has been published [85]. In this review, the interactions of p11 with additional viruses and bacteria are also comprehensively summarized. ...
p11 (S100A10, annexin II light chain, calpactin I light chain) is a multifunctional protein that forms a heterotetrameric complex with Annexin A2, particularly at cell membranes. p11, alone or together with Annexin A2, interacts with several ion channels and receptors and regulates their cellular localization and function. Altered levels of p11 are implicated in the pathophysiology of several forms of cancer, psychiatric disorders, and neurodegeneration. Via interactions with ion channels and receptors, p11 modulates therapeutic actions of drugs targeting brain disorders. By serving as a plasminogen receptor, p11 plays an important role in plasmin generation, fibrinolysis, angiogenesis, tumor progression, and metastasis. Here, we review mechanisms whereby p11 regulates functions of ion channels and receptors in health and disease states.
... Two phospholipid binding proteins were also detected as differentially regulated annexin A1 and A5, and the differential expression of one of them (annexin A1) was validated by western blot analysis. Annexins bind to negatively charged phospholipids in a calcium dependent manner and they have recently been shown to play significant roles in host-cell pathogen interactions [41]. While annexin A1 has been shown to play a pro-viral role in influenza A virus infection [42] with involvement at several stages of the influenza A replication cycle, it has been shown to negatively regulate hepatitis C replication [43]. ...
Zika virus (ZIKV) has been endemic in Southeast Asian countries for several years, but the presence of the virus has not been associated with significant outbreaks of infection unlike other countries around the world where the Asian lineage ZIKV was introduced recently. However, few studies have been undertaken using the endemic virus. The Thai isolate was shown to have a similar tissue tropism to an African isolate of ZIKV, albeit that the Thai isolate infected cells at a lower level as compared to the African isolate. To further understand the pathogenesis of the Thai isolate, a 2D-gel proteomic analysis was undertaken of ZIKV infected LLC-MK2 cells. Seven proteins (superoxide dismutase [Mn], peroxiredoxin 2, ATP synthase subunit alpha, annexin A5 and annexin A1, carnitine o-palmitoyltransferase 2 and cytoskeleton-associated protein 2) were identified as differentially regulated. Of four proteins selected for validation, three (superoxide dismutase [Mn], peroxiredoxin 2, ATP synthase subunit alpha, and annexin A1) were shown to be differentially regulated at both the transcriptional and translational levels. The proteins identified were primarily involved in energy production both directly, and indirectly through mediation of autophagy, as well as in the response to oxidative stress, possibly occurring as a consequence of increased energy production. This study provides further new information on the pathogenesis of ZIKV.
... Diverse functions have been linked to annexin family members in vertebrates. For a comprehensive overview, the interested reader is referred to more extensive reviews covering these topics (Enrich, Rentero, Meneses-Salas, Tebar, & Grewal, 2017;Gerke et al., 2005;Grewal, Wason, Enrich, & Rentero, 2016;Kuehnl, Musiol, Raabe, & Rescher, 2016;Moss & Morgan, 2004;Perretti & D'Acquisto, 2009;. Most of the annexin functions are connected to membrane related events. ...
Plasma membrane wound repair is a cell-autonomous process that is triggered by Ca2+ entering through the site of injury and involves membrane resealing, i.e., re-establishment of a continuous plasma membrane, as well as remodeling of the cortical actin cytoskeleton. Among other things, the injury-induced Ca2+ elevation initiates the wound site recruitment of Ca2+-regulated proteins that function in the course of repair. Annexins are a class of such Ca2+-regulated proteins. They associate with acidic phospholipids of cellular membranes in their Ca2+ bound conformation with Ca2+ sensitivities ranging from the low to high micromolar range depending on the respective annexin protein. Annexins accumulate at sites of plasma membrane injury in a temporally controlled manner and are thought to function by controlling membrane rearrangements at the wound site, most likely in conjunction with other repair proteins such as dysferlin. Their role in membrane repair, which has been evidenced in several model systems, will be discussed in this chapter.
... The inability of vaccines to induce broad range protection against IAV in circulation, and a possible event of a mutated virus coming into circulation makes the development of therapies that enhance host antiviral mechanisms very desirable. Over the years, considerable efforts have been spent on understanding the roles of various ANX molecules in several infectious diseases, which has been carefully reviewed (Kuehnl et al., 2016;Schloer et al., 2018). To this effect, it can be concluded that ANXs represent very important molecules that are potential targets for further development in the treatment of IAV (Figure 2). ...
Influenza A viruses (IAVs) are important human respiratory pathogens which cause seasonal or periodic endemic infections. IAV can result in severe or fatal clinical complications including pneumonia and respiratory distress syndrome. Treatment of IAV infections is complicated because the virus can evade host immunity through antigenic drifts and antigenic shifts, to establish infections making new treatment options desirable. Annexins (ANXs) are a family of calcium and phospholipid binding proteins with immunomodulatory roles in viral infections, lung injury, and inflammation. A current understanding of the role of ANXs in modulating IAV infection and host responses will enable the future development of more effective antiviral therapies. This review presents a comprehensive understanding of the advances made in the field of ANXs, in particular, ANXA1 and IAV research and highlights the importance of ANXs as a suitable target for IAV therapy.
... Aghazadeh and Papadopoulos, 2016); (3) Annexin families that are involved in trafficking and organization of endocytosis, vesicles, exocytosis, and calcium ion channel formation (Grieve et al., 2012;Kuehnl et al., 2016); (4) MAP kinase families, which play critical roles in signal transduction, phosphorylation and activation of MAPK1/ERK2 and MAPK3/ERK1 pathways (Vomastek et al., 2008;Robinson and Pitcher, 2013;Cook et al., 2017). Further functional analysis confirmed that the candidate host proteins were strongly associated with cytoplasmic vesicle membranes, mitochondrial membranes, mitochondria, the COP9 signalosome, and phospholipid binding, and connected with antigen binding, viral endocytosis, transportation, anti-virus responses, and viral budding (Bech-Otschir et al., 2001;Horner et al., 2011;van Zuylen et al., 2012;Richard et al., 2015). ...
Ebolavirus (EBOV) life cycle involves interactions with numerous host factors, but it remains poorly understood, as does pathogenesis. Herein, we synthesized 65 siRNAs targeting host genes mostly connected with aspects of the negative-sense RNA virus life cycle (including viral entry, uncoating, fusion, replication, assembly, and budding). We produced EBOV transcription- and replication-competent virus-like particles (trVLPs) to mimic the EBOV life cycle. After screening host factors associated with the trVLP life cycle, we assessed interactions of host proteins with trVLP glycoprotein (GP), VP40, and RNA by co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP). The results demonstrate that RNAi silencing with 11 siRNAs (ANXA5, ARFGAP1, FLT4, GRP78, HSPA1A, HSP90AB1, HSPA8, MAPK11, MEK2, NTRK1, and YWHAZ) decreased the replication efficiency of trVLPs. Co-IP revealed nine candidate host proteins (FLT4, GRP78, HSPA1A, HSP90AB1, HSPA8, MAPK11, MEK2, NTRK1, and YWHAZ) potentially interacting with trVLP GP, and four (ANXA5, GRP78, HSPA1A, and HSP90AB1) potentially interacting with trVLP VP40. Ch-IP identified nine candidate host proteins (ANXA5, ARFGAP1, FLT4, GRP78, HSPA1A, HSP90AB1, MAPK11, MEK2, and NTRK1) interacting with trVLP RNA. This study was based on trVLP and could not replace live ebolavirus entirely; in particular, the interaction between trVLP RNA and host proteins cannot be assumed to be identical in live virus. However, the results provide valuable information for further studies and deepen our understanding of essential host factors involved in the EBOV life cycle.
... Not surprisingly, annexins have been implicated in the regulation of a broad range of cellular and physiological processes that are linked to cellular membranes, such as vesicle organization, membrane trafficking and scaffolding, endo-and exocytosis, and membrane/cytoskeleton interactions [16][17][18][19][20][21]. Membrane dynamics is also a recurrent theme in host-pathogen interactions, and annexins might function as host cell-derived auxiliary proteins in shaping the microbe-host interplay [22]. In recent years, a growing number of annexin knock out (KO) mouse models have been constructed [23], and they will certainly prove to be useful tools for investigating annexin functions, both as drugs and therapeutic targets. ...
The vertebrate annexin superfamily (AnxA) consists of 12 members of a calcium (Ca²⁺) and phospholipid binding protein family which share a high structural homology. In keeping with this hallmark feature, annexins have been implicated in the Ca²⁺-controlled regulation of a broad range of membrane events. In this review, we identify and discuss several themes of annexin actions that hold a potential therapeutic value, namely, the regulation of the immune response and the control of tissue homeostasis, and that repeatedly surface in the annexin activity profile. Our aim is to identify and discuss those annexin properties which might be exploited from a translational science and specifically, a clinical point of view.
... Not surprisingly, annexins have been implicated in the regulation of a broad range of cellular and physiological processes that are linked to cellular membranes, such as vesicle organization, membrane trafficking and scaffolding, endoand exocytosis, and membrane/cytoskeleton interactions [16][17][18][19][20][21]. Membrane dynamics is also a recurrent theme in host-pathogen interactions, and annexins might function as host cell-derived auxiliary proteins in shaping the microbe-host interplay [22]. In recent years, a growing number of annexin knock out (KO) mouse models have been constructed [23], and they will certainly prove to be useful tools for investigating annexin functions, both as drugs and therapeutic targets. ...
The vertebrate annexin superfamily (AnxA) consists of 12 members of a calcium (Ca2+) and phospholipid binding protein family which share a high structural homology. In keeping with this hallmark feature, annexins have been implicated in the Ca2+-controlled regulation of a broad range of membrane events. In this review, we identify and discuss several themes of annexin actions that hold a potential therapeutic value, namely the regulation of the immune response and the control of tissue homeostasis, and that repeatedly surface in the annexin activity profile. Our aim is to identify and discuss those annexin properties which might be exploited from a translational science and specifically clinical point of view.
