Special Issue "Recent Developments in Annexin Biology"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 May 2020).

Special Issue Editors

Dr. Jyoti K. Jaiswal
Website
Guest Editor
Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, and Children's National Research Institute, 111 Michigan Avenue NW, Washington, DC 20010, USA
Interests: calcium; cell imaging; injury and repair; inflammation; membrane trafficking; mitochondria; muscle biology
Dr. Volker Gerke
Website
Guest Editor
Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation, University of Münster, Von-Esmarch-Strasse 56, 48149 Münster, Germany
Interests: membrane organization and dynamics; exo- and endocytosis; calcium-binding proteins; lipid-protein interactions
Dr. Ursula Rescher
Website
Guest Editor
Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation, University of Muenster, Von-Esmarch-Street 56, D-48149 Muenster, Germany
Interests: cell autonomous and innate immune defense; innate immune sensing; endosomal Ca2+ regulation; annexins
Special Issues and Collections in MDPI journals
Dr. Lina Hsiu Kim Lim
Website
Guest Editor
Yong Loo Lin School of Medicine, Singapore City, Singapore
Interests: tumor microenvironment; tumor immunology; innate immunity; stress and inflammation

Special Issue Information

Dear Colleagues,

To mark Annexins 2019, the 10th anniversary meeting of the biennial conference on Annexins, this Special Issue is aimed at sharing a sample of the recent advances in Annexin Biology that were presented at this meeting. With over 40 years since the discovery of Annexins, these proteins first identified for their calcium and membrane binding abilities continue to be recognized for their roles in a wide variety of biological processes. As the variety of biological processes that Annexins play a role in continues to expand, there is a growing need for understanding the properties and function of Annexins. The  findings presented at the Annexins 2019 meeting offered such mechanistic insights into Annexin properties and into the role of these proteins in processes ranging from microbial infection, cell and tissue injury to inflammation and cancer, to name a few. While several other interesting biological aspects of Annexins were also discussed at the meeting, these were by no means exhaustive enough to cover all of the roles of Annexins that have been identified. The compilation of the findings and perspectives presented at this meeting and included in this Special Issue is intended to share these findings with a wider audience and encourage broad participation in understanding these abundant and omnipresent proteins that are still not fully understood. 

Prof. Jyoti K. Jaiswal
Dr. Volker Gerke
Dr. Ursula Rescher
Dr. Lina Hsiu Kim Lim
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Annexin
  • Calcium
  • Cancer
  • Diseases
  • Infection
  • Inflammation
  • Injury
  • Innate immunity
  • Membrane
  • Pathogen

Published Papers (10 papers)

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Research

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Open AccessArticle
Expression of Annexin A2 Promotes Cancer Progression in Estrogen Receptor Negative Breast Cancers
Cells 2020, 9(7), 1582; https://doi.org/10.3390/cells9071582 - 30 Jun 2020
Abstract
When breast cancer progresses to a metastatic stage, survival rates decline rapidly and it is considered incurable. Thus, deciphering the critical mechanisms of metastasis is of vital importance to develop new treatment options. We hypothesize that studying the proteins that are newly synthesized [...] Read more.
When breast cancer progresses to a metastatic stage, survival rates decline rapidly and it is considered incurable. Thus, deciphering the critical mechanisms of metastasis is of vital importance to develop new treatment options. We hypothesize that studying the proteins that are newly synthesized during the metastatic processes of migration and invasion will greatly enhance our understanding of breast cancer progression. We conducted a mass spectrometry screen following bioorthogonal noncanonical amino acid tagging to elucidate changes in the nascent proteome that occur during epidermal growth factor stimulation in migrating and invading cells. Annexin A2 was identified in this screen and subsequent examination of breast cancer cell lines revealed that Annexin A2 is specifically upregulated in estrogen receptor negative (ER-) cell lines. Furthermore, siRNA knockdown showed that Annexin A2 expression promotes the proliferation, wound healing and directional migration of breast cancer cells. In patients, Annexin A2 expression is increased in ER- breast cancer subtypes. Additionally, high Annexin A2 expression confers a higher probability of distant metastasis specifically for ER- patients. This work establishes a pivotal role of Annexin A2 in breast cancer progression and identifies Annexin A2 as a potential therapeutic target for the more aggressive and harder to treat ER- subtype. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)
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Open AccessFeature PaperArticle
RNA-Sequencing-Based Transcriptomic Analysis Reveals a Role for Annexin-A1 in Classical and Influenza A Virus-Induced Autophagy
Cells 2020, 9(6), 1399; https://doi.org/10.3390/cells9061399 - 04 Jun 2020
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)
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Open AccessArticle
Annexin A1/Formyl Peptide Receptor Pathway Controls Uterine Receptivity to the Blastocyst
Cells 2020, 9(5), 1188; https://doi.org/10.3390/cells9051188 - 11 May 2020
Abstract
Embryo implantation into the uterine wall is a highly modulated, complex process. We previously demonstrated that Annexin A1 (AnxA1), which is a protein secreted by epithelial and inflammatory cells in the uterine microenvironment, controls embryo implantation in vivo. Here, we decipher the effects [...] Read more.
Embryo implantation into the uterine wall is a highly modulated, complex process. We previously demonstrated that Annexin A1 (AnxA1), which is a protein secreted by epithelial and inflammatory cells in the uterine microenvironment, controls embryo implantation in vivo. Here, we decipher the effects of recombinant AnxA1 in this phenomenon by using human trophoblast cell (BeWo) spheroids and uterine epithelial cells (Ishikawa; IK). AnxA1-treated IK cells demonstrated greater levels of spheroid adherence and upregulation of the tight junction molecules claudin-1 and zona occludens-1, as well as the glycoprotein mucin-1 (Muc-1). The latter effect of AnxA1 was not mediated through IL-6 secreted from IK cells, a known inducer of Muc-1 expression. Rather, these effects of AnxA1 involved activation of the formyl peptide receptors FPR1 and FPR2, as pharmacological blockade of FPR1 or FPR1/FPR2 abrogated such responses. The downstream actions of AnxA1 were mediated through the ERK1/2 phosphorylation pathway and F-actin polymerization in IK cells, as blockade of ERK1/2 phosphorylation reversed AnxA1-induced Muc-1 and claudin-1 expression. Moreover, FPR2 activation by AnxA1 induced vascular endothelial growth factor (VEGF) secretion by IK cells, and the supernatant of AnxA1-treated IK cells evoked angiogenesis in vitro. In conclusion, these data highlight the role of the AnxA1/FPR1/FPR2 pathway in uterine epithelial control of blastocyst implantation. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)
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Open AccessArticle
Membrane Binding Promotes Annexin A2 Oligomerization
Cells 2020, 9(5), 1169; https://doi.org/10.3390/cells9051169 - 08 May 2020
Abstract
Annexin A2 (AnxA2) is a cytosolic Ca2+ regulated membrane binding protein that can induce lipid domain formation and plays a role in exocytosis and endocytosis. To better understand the mode of annexin-membrane interaction, we analyzed membrane-bound AnxA2 assemblies by employing a novel [...] Read more.
Annexin A2 (AnxA2) is a cytosolic Ca2+ regulated membrane binding protein that can induce lipid domain formation and plays a role in exocytosis and endocytosis. To better understand the mode of annexin-membrane interaction, we analyzed membrane-bound AnxA2 assemblies by employing a novel 3-armed chemical crosslinker and specific AnxA2 mutant proteins. Our data show that AnxA2 forms crosslinkable oligomers upon binding to membranes containing negatively charged phospholipids. AnxA2 mutants with amino acid substitutions in residues predicted to be involved in lateral protein–protein interaction show compromised oligomer formation, albeit still being capable of binding to negatively charged membranes in the presence of Ca2+. These results suggest that lateral protein–protein interactions are involved in the formation of AnxA2 clusters on a biological membrane. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)
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Open AccessArticle
Selective Degradation Permits a Feedback Loop Controlling Annexin A6 and Cholesterol Levels in Endolysosomes of NPC1 Mutant Cells
Cells 2020, 9(5), 1152; https://doi.org/10.3390/cells9051152 - 07 May 2020
Abstract
We recently identified elevated annexin A6 (AnxA6) protein levels in Niemann–Pick-type C1 (NPC1) mutant cells. In these cells, AnxA6 depletion rescued the cholesterol accumulation associated with NPC1 deficiency. Here, we demonstrate that elevated AnxA6 protein levels in NPC1 mutants or upon pharmacological NPC1 [...] Read more.
We recently identified elevated annexin A6 (AnxA6) protein levels in Niemann–Pick-type C1 (NPC1) mutant cells. In these cells, AnxA6 depletion rescued the cholesterol accumulation associated with NPC1 deficiency. Here, we demonstrate that elevated AnxA6 protein levels in NPC1 mutants or upon pharmacological NPC1 inhibition, using U18666A, were not due to upregulated AnxA6 mRNA expression, but caused by defects in AnxA6 protein degradation. Two KFERQ-motifs are believed to target AnxA6 to lysosomes for chaperone-mediated autophagy (CMA), and we hypothesized that the cholesterol accumulation in endolysosomes (LE/Lys) triggered by the NPC1 inhibition could interfere with the CMA pathway. Therefore, AnxA6 protein amounts and cholesterol levels in the LE/Lys (LE-Chol) compartment were analyzed in NPC1 mutant cells ectopically expressing lysosome-associated membrane protein 2A (Lamp2A), which is well known to induce the CMA pathway. Strikingly, AnxA6 protein amounts were strongly decreased and coincided with significantly reduced LE-Chol levels in NPC1 mutant cells upon Lamp2A overexpression. Therefore, these findings suggest Lamp2A-mediated restoration of CMA in NPC1 mutant cells to lower LE-Chol levels with concomitant lysosomal AnxA6 degradation. Collectively, we propose CMA to permit a feedback loop between AnxA6 and cholesterol levels in LE/Lys, encompassing a novel mechanism for regulating cholesterol homeostasis in NPC1 disease. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)
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Open AccessFeature PaperArticle
Exploring Biased Agonism at FPR1 as a Means to Encode Danger Sensing
Cells 2020, 9(4), 1054; https://doi.org/10.3390/cells9041054 - 23 Apr 2020
Abstract
Ligand-based selectivity in signal transduction (biased signaling) is an emerging field of G protein-coupled receptor (GPCR) research and might allow the development of drugs with targeted activation profiles. Human formyl peptide receptor 1 (FPR1) is a GPCR that detects potentially hazardous states characterized [...] Read more.
Ligand-based selectivity in signal transduction (biased signaling) is an emerging field of G protein-coupled receptor (GPCR) research and might allow the development of drugs with targeted activation profiles. Human formyl peptide receptor 1 (FPR1) is a GPCR that detects potentially hazardous states characterized by the appearance of N-formylated peptides that originate from either bacteria or mitochondria during tissue destruction; however, the receptor also responds to several non-formylated agonists from various sources. We hypothesized that an additional layer of FPR signaling is encoded by biased agonism, thus allowing the discrimination of the source of threat. We resorted to the comparative analysis of FPR1 agonist-evoked responses across three prototypical GPCR signaling pathways, i.e., the inhibition of cAMP formation, receptor internalization, and ERK activation, and analyzed cellular responses elicited by several bacteria- and mitochondria-derived ligands. We also included the anti-inflammatory annexinA1 peptide Ac2-26 and two synthetic ligands, the W-peptide and the small molecule FPRA14. Compared to the endogenous agonists, the bacterial agonists displayed significantly higher potencies and efficacies. Selective pathway activation was not observed, as both groups were similarly biased towards the inhibition of cAMP formation. The general agonist bias in FPR1 signaling suggests a source-independent pathway selectivity for transmission of pro-inflammatory danger signaling. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)
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Open AccessArticle
The Essential Role of anxA2 in Langerhans Cell Birbeck Granules Formation
Cells 2020, 9(4), 974; https://doi.org/10.3390/cells9040974 - 15 Apr 2020
Abstract
Langerhans cells (LC) are the resident antigen presenting cells of the mucosal epithelium and play an essential role in initiating immune responses. LC are the only cells in the body to contain Birbeck granules (BG), which are unique cytoplasmic organelles comprised of c-type [...] Read more.
Langerhans cells (LC) are the resident antigen presenting cells of the mucosal epithelium and play an essential role in initiating immune responses. LC are the only cells in the body to contain Birbeck granules (BG), which are unique cytoplasmic organelles comprised of c-type lectin langerin. Studies of BG have historically focused on morphological characterizations, but BG have also been implicated in viral antigen processing which suggests that they can serve a function in antiviral immunity. This study focused on investigating proteins that could be involved in BG formation to further characterize their structure using transmission electron microscopy (TEM). Here, we report a critical role for the protein annexin A2 (anxA2) in the proper formation of BG structures. When anxA2 expression is downregulated, langerin expression decreases, cytoplasmic BG are nearly ablated, and the presence of malformed BG-like structures increases. Furthermore, in the absence of anxA2, we found langerin was no longer localized to BG or BG-like structures. Taken together, these results indicate an essential role for anxA2 in facilitating the proper formation of BG. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)
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Open AccessArticle
Annexin A1 Regulates NLRP3 Inflammasome Activation and Modifies Lipid Release Profile in Isolated Peritoneal Macrophages
Cells 2020, 9(4), 926; https://doi.org/10.3390/cells9040926 - 09 Apr 2020
Abstract
Annexin A1 (AnxA1) is a potent anti-inflammatory protein that downregulates proinflammatory cytokine release. This study evaluated the role of AnxA1 in the regulation of NLRP3 inflammasome activation and lipid release by starch-elicited murine peritoneal macrophages. C57bl/6 wild-type (WT) and AnxA1-null (AnxA1-/-) [...] Read more.
Annexin A1 (AnxA1) is a potent anti-inflammatory protein that downregulates proinflammatory cytokine release. This study evaluated the role of AnxA1 in the regulation of NLRP3 inflammasome activation and lipid release by starch-elicited murine peritoneal macrophages. C57bl/6 wild-type (WT) and AnxA1-null (AnxA1-/-) mice received an intraperitoneal injection of 1.5% starch solution for macrophage recruitment. NLRP3 was activated by priming cells with lipopolysaccharide for 3 h, followed by nigericin (1 h) or ATP (30 min) incubation. As expected, nigericin and ATP administration decreased elicited peritoneal macrophage viability and induced IL-1β release, more pronounced in the AnxA1-/- cells than in the control peritoneal macrophages. In addition, nigericin-activated AnxA1-/- macrophages showed increased levels of NLRP3, while points of co-localization of the AnxA1 protein and NLRP3 inflammasome were detected in WT cells, as demonstrated by ultrastructural analysis. The lipidomic analysis showed a pronounced release of prostaglandins in nigericin-stimulated WT peritoneal macrophages, while ceramides were detected in AnxA1-/- cell supernatants. Different eicosanoid profiles were detected for both genotypes, and our results suggest that endogenous AnxA1 regulates the NLRP3-derived IL-1β and lipid mediator release in macrophages. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)
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Review

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Open AccessFeature PaperReview
Annexin A2 in Inflammation and Host Defense
Cells 2020, 9(6), 1499; https://doi.org/10.3390/cells9061499 - 19 Jun 2020
Abstract
Annexin A2 (AnxA2) is a multifunctional calcium2+ (Ca2+) and phospholipid-binding protein that is expressed in a wide spectrum of cells, including those participating in the inflammatory response. In acute inflammation, the interaction of AnxA2 with actin and adherens junction VE-cadherins [...] Read more.
Annexin A2 (AnxA2) is a multifunctional calcium2+ (Ca2+) and phospholipid-binding protein that is expressed in a wide spectrum of cells, including those participating in the inflammatory response. In acute inflammation, the interaction of AnxA2 with actin and adherens junction VE-cadherins underlies its role in regulating vascular integrity. In addition, its contribution to endosomal membrane repair impacts several aspects of inflammatory regulation, including lysosome repair, which regulates inflammasome activation, and autophagosome biogenesis, which is essential for macroautophagy. On the other hand, AnxA2 may be co-opted to promote adhesion, entry, and propagation of bacteria or viruses into host cells. In the later stages of acute inflammation, AnxA2 contributes to the initiation of angiogenesis, which promotes tissue repair, but, when dysregulated, may also accompany chronic inflammation. AnxA2 is overexpressed in malignancies, such as breast cancer and glioblastoma, and likely contributes to cancer progression in the context of an inflammatory microenvironment. We conclude that annexin AnxA2 normally fulfills a spectrum of anti-inflammatory functions in the setting of both acute and chronic inflammation but may contribute to disease states in settings of disordered homeostasis. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)
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Open AccessReview
Interdisciplinary Synergy to Reveal Mechanisms of Annexin-Mediated Plasma Membrane Shaping and Repair
Cells 2020, 9(4), 1029; https://doi.org/10.3390/cells9041029 - 21 Apr 2020
Abstract
The plasma membrane surrounds every single cell and essentially shapes cell life by separating the interior from the external environment. Thus, maintenance of cell membrane integrity is essential to prevent death caused by disruption of the plasma membrane. To counteract plasma membrane injuries, [...] Read more.
The plasma membrane surrounds every single cell and essentially shapes cell life by separating the interior from the external environment. Thus, maintenance of cell membrane integrity is essential to prevent death caused by disruption of the plasma membrane. To counteract plasma membrane injuries, eukaryotic cells have developed efficient repair tools that depend on Ca2+- and phospholipid-binding annexin proteins. Upon membrane damage, annexin family members are activated by a Ca2+ influx, enabling them to quickly bind at the damaged membrane and facilitate wound healing. Our recent studies, based on interdisciplinary research synergy across molecular cell biology, experimental membrane physics, and computational simulations show that annexins have additional biophysical functions in the repair response besides enabling membrane fusion. Annexins possess different membrane-shaping properties, allowing for a tailored response that involves rapid bending, constriction, and fusion of membrane edges for resealing. Moreover, some annexins have high affinity for highly curved membranes that appear at free edges near rupture sites, a property that might accelerate their recruitment for rapid repair. Here, we discuss the mechanisms of annexin-mediated membrane shaping and curvature sensing in the light of our interdisciplinary approach to study plasma membrane repair. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)
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