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Recent Developments in Annexin Biology
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Recent Developments in Annexin Biology

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Intracellular and Plasma Membranes".

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 64511

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Jyoti K. Jaiswal

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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

E-Mail 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
Prof. Dr. Ursula Rescher

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Guest Editor
Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, University of Münster, Von-Esmarch-Straße 56, D-48149 Münster, Germany
Interests: host–pathogen interactions; host intracellular compartments; drug repurposing
Special Issues, Collections and Topics in MDPI journals
Dr. Lina Hsiu Kim Lim

E-Mail 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

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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 semimonthly 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 2700 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 (16 papers)

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Editorial

Jump to: Research, Review

4 pages, 197 KiB  
Editorial
Special Issue “Recent Developments in Annexin Biology”
by Ursula Rescher, Volker Gerke, Lina Hsiu Kim Lim and Jyoti K. Jaiswal
Cells 2020, 9(11), 2477; https://doi.org/10.3390/cells9112477 - 14 Nov 2020
Viewed by 2122
Abstract
Discovered over 40 years ago, the annexin proteins were found to be a structurally conserved subgroup of Ca2+-binding proteins. While the initial research on annexins focused on their signature feature of Ca2+-dependent binding to membranes, over the years the [...] Read more.
Discovered over 40 years ago, the annexin proteins were found to be a structurally conserved subgroup of Ca2+-binding proteins. While the initial research on annexins focused on their signature feature of Ca2+-dependent binding to membranes, over the years the biennial Annexin conference series has highlighted additional diversity in the functions attributed to the annexin family of proteins. The roles of these proteins now extend from basic science to biomedical research, and are being translated into the clinic. The research on annexins involves a global network of researchers, and the 10th biennial Annexin conference brought together over 80 researchers from ten European countries, USA, Brazil, Singapore, Japan and Australia for 3 days in September 2019. In this conference, the discussions focused on two distinct themes—the role of annexins in cellular organization and in health and disease. The articles published in this Special Issue cover these two main themes discussed at this conference, offering a glimpse into some of the notable findings in the field of annexin biology. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)

Research

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18 pages, 4463 KiB  
Article
Targeting AnxA1/Formyl Peptide Receptor 2 Pathway Affords Protection against Pathological Thrombo-Inflammation
by Shantel A. Vital, Elena Y. Senchenkova, Junaid Ansari and Felicity N. E. Gavins
Cells 2020, 9(11), 2473; https://doi.org/10.3390/cells9112473 - 13 Nov 2020
Cited by 25 | Viewed by 3584
Abstract
Stroke is a leading cause of death and disability globally and is associated with a number of co-morbidities including sepsis and sickle cell disease (SCD). Despite thrombo-inflammation underlying these co-morbidities, its pathogenesis remains complicated and drug discovery programs aimed at reducing and resolving [...] Read more.
Stroke is a leading cause of death and disability globally and is associated with a number of co-morbidities including sepsis and sickle cell disease (SCD). Despite thrombo-inflammation underlying these co-morbidities, its pathogenesis remains complicated and drug discovery programs aimed at reducing and resolving the detrimental effects remain a major therapeutic challenge. The objective of this study was to assess whether the anti-inflammatory pro-resolving protein Annexin A1 (AnxA1) was able to reduce inflammation-induced thrombosis and suppress platelet activation and thrombus formation in the cerebral microvasculature. Using two distinct models of pathological thrombo-inflammation (lipopolysaccharide (LPS) and sickle transgenic mice (STM)), thrombosis was induced in the murine brain using photoactivation (light/dye) coupled with intravital microscopy. The heightened inflammation-induced microvascular thrombosis present in these two distinct thrombo-inflammatory models was inhibited significantly by the administration of AnxA1 mimetic peptide AnxA1Ac2-26 (an effect more pronounced in the SCD model vs. the endotoxin model) and mediated by the key resolution receptor, Fpr2/ALX. Furthermore, AnxA1Ac2-26 treatment was able to hamper platelet aggregation by reducing platelet stimulation and aggregation (by moderating αIIbβ3 and P-selectin). These findings suggest that targeting the AnxA1/Fpr2/ALX pathway represents an attractive novel treatment strategy for resolving thrombo-inflammation, counteracting e.g., stroke in high-risk patient cohorts. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)
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14 pages, 2564 KiB  
Article
Annexin A2 Egress during Calcium-Regulated Exocytosis in Neuroendocrine Cells
by Marion Gabel, Cathy Royer, Tamou Thahouly, Valérie Calco, Stéphane Gasman, Marie-France Bader, Nicolas Vitale and Sylvette Chasserot-Golaz
Cells 2020, 9(9), 2059; https://doi.org/10.3390/cells9092059 - 09 Sep 2020
Cited by 7 | Viewed by 3102
Abstract
Annexin A2 (AnxA2) is a calcium- and lipid-binding protein involved in neuroendocrine secretion where it participates in the formation and/or stabilization of lipid micro-domains required for structural and spatial organization of the exocytotic machinery. We have recently described that phosphorylation of AnxA2 on [...] Read more.
Annexin A2 (AnxA2) is a calcium- and lipid-binding protein involved in neuroendocrine secretion where it participates in the formation and/or stabilization of lipid micro-domains required for structural and spatial organization of the exocytotic machinery. We have recently described that phosphorylation of AnxA2 on Tyr23 is critical for exocytosis. Considering that Tyr23 phosphorylation is known to promote AnxA2 externalization to the outer face of the plasma membrane in different cell types, we examined whether this phenomenon occurred in neurosecretory chromaffin cells. Using immunolabeling and biochemical approaches, we observed that nicotine stimulation triggered the egress of AnxA2 to the external leaflets of the plasma membrane in the vicinity of exocytotic sites. AnxA2 was found co-localized with tissue plasminogen activator, previously described on the surface of chromaffin cells following secretory granule release. We propose that AnxA2 might be a cell surface tissue plasminogen activator receptor for chromaffin cells, thus playing a role in autocrine or paracrine regulation of exocytosis. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)
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Graphical abstract

17 pages, 3771 KiB  
Article
Annexin A2 Mediates Dysferlin Accumulation and Muscle Cell Membrane Repair
by Daniel C. Bittel, Goutam Chandra, Laxmi M. S. Tirunagri, Arun B. Deora, Sushma Medikayala, Luana Scheffer, Aurelia Defour and Jyoti K. Jaiswal
Cells 2020, 9(9), 1919; https://doi.org/10.3390/cells9091919 - 19 Aug 2020
Cited by 29 | Viewed by 4417
Abstract
Muscle cell plasma membrane is frequently damaged by mechanical activity, and its repair requires the membrane protein dysferlin. We previously identified that, similar to dysferlin deficit, lack of annexin A2 (AnxA2) also impairs repair of skeletal myofibers. Here, we have studied the mechanism [...] Read more.
Muscle cell plasma membrane is frequently damaged by mechanical activity, and its repair requires the membrane protein dysferlin. We previously identified that, similar to dysferlin deficit, lack of annexin A2 (AnxA2) also impairs repair of skeletal myofibers. Here, we have studied the mechanism of AnxA2-mediated muscle cell membrane repair in cultured muscle cells. We find that injury-triggered increase in cytosolic calcium causes AnxA2 to bind dysferlin and accumulate on dysferlin-containing vesicles as well as with dysferlin at the site of membrane injury. AnxA2 accumulates on the injured plasma membrane in cholesterol-rich lipid microdomains and requires Src kinase activity and the presence of cholesterol. Lack of AnxA2 and its failure to translocate to the plasma membrane, both prevent calcium-triggered dysferlin translocation to the plasma membrane and compromise repair of the injured plasma membrane. Our studies identify that Anx2 senses calcium increase and injury-triggered change in plasma membrane cholesterol to facilitate dysferlin delivery and repair of the injured plasma membrane. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)
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20 pages, 4288 KiB  
Article
Annexin-A6 in Membrane Repair of Human Skeletal Muscle Cell: A Role in the Cap Subdomain
by Coralie Croissant, Céline Gounou, Flora Bouvet, Sisareuth Tan and Anthony Bouter
Cells 2020, 9(7), 1742; https://doi.org/10.3390/cells9071742 - 21 Jul 2020
Cited by 26 | Viewed by 3362
Abstract
Defects in membrane repair contribute to the development of some muscular dystrophies, highlighting the importance to decipher the membrane repair mechanisms in human skeletal muscle. In murine myofibers, the formation of a cap subdomain composed notably by annexins (Anx) is critical for membrane [...] Read more.
Defects in membrane repair contribute to the development of some muscular dystrophies, highlighting the importance to decipher the membrane repair mechanisms in human skeletal muscle. In murine myofibers, the formation of a cap subdomain composed notably by annexins (Anx) is critical for membrane repair. We applied membrane damage by laser ablation to human skeletal muscle cells and assessed the behavior of annexin-A6 (AnxA6) tagged with GFP by correlative light and electron microscopy (CLEM). We show that AnxA6 was recruited to the site of membrane injury within a few seconds after membrane injury. In addition, we show that the deficiency in AnxA6 compromises human sarcolemma repair, demonstrating the crucial role played by AnxA6 in this process. An AnxA6-containing cap-subdomain was formed in damaged human myotubes in about one minute. Through transmission electron microscopy (TEM), we observed that extension of the sarcolemma occurred during membrane resealing, which participated in forming a dense lipid structure in order to plug the hole. By properties of membrane folding and curvature, AnxA6 helped in the formation of this tight structure. The compaction of intracellular membranes—which are used for membrane resealing and engulfed in extensions of the sarcolemma—may also facilitate elimination of the excess of lipid and protein material once cell membrane has been repaired. These data reinforce the role played by AnxA6 and the cap subdomain in membrane repair of skeletal muscle cells. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)
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Graphical abstract

24 pages, 2390 KiB  
Article
Expression of Annexin A2 Promotes Cancer Progression in Estrogen Receptor Negative Breast Cancers
by Amira F. Mahdi, Beatrice Malacrida, Joanne Nolan, Mary E. McCumiskey, Anne B. Merrigan, Ashish Lal, Shona Tormey, Aoife J. Lowery, Kieran McGourty and Patrick A. Kiely
Cells 2020, 9(7), 1582; https://doi.org/10.3390/cells9071582 - 30 Jun 2020
Cited by 13 | Viewed by 3455
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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15 pages, 3163 KiB  
Article
RNA-Sequencing-Based Transcriptomic Analysis Reveals a Role for Annexin-A1 in Classical and Influenza A Virus-Induced Autophagy
by Jianzhou Cui, Dhakshayini Morgan, Dao Han Cheng, Sok Lin Foo, Gracemary L. R. Yap, Patrick B. Ampomah, Suruchi Arora, Karishma Sachaphibulkij, Balamurugan Periaswamy, Anna-Marie Fairhurst, Paola Florez De Sessions and Lina H. K. Lim
Cells 2020, 9(6), 1399; https://doi.org/10.3390/cells9061399 - 04 Jun 2020
Cited by 8 | Viewed by 3819
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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17 pages, 3114 KiB  
Article
Annexin A1/Formyl Peptide Receptor Pathway Controls Uterine Receptivity to the Blastocyst
by Cristina B. Hebeda, Silvana Sandri, Cláudia M. Benis, Marina de Paula-Silva, Rodrigo A. Loiola, Chris Reutelingsperger, Mauro Perretti and Sandra H. P. Farsky
Cells 2020, 9(5), 1188; https://doi.org/10.3390/cells9051188 - 11 May 2020
Cited by 18 | Viewed by 3980
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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Graphical abstract

12 pages, 2147 KiB  
Article
Membrane Binding Promotes Annexin A2 Oligomerization
by Anna Lívia Linard Matos, Sergej Kudruk, Johanna Moratz, Milena Heflik, David Grill, Bart Jan Ravoo and Volker Gerke
Cells 2020, 9(5), 1169; https://doi.org/10.3390/cells9051169 - 08 May 2020
Cited by 10 | Viewed by 3740
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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Graphical abstract

16 pages, 2449 KiB  
Article
Selective Degradation Permits a Feedback Loop Controlling Annexin A6 and Cholesterol Levels in Endolysosomes of NPC1 Mutant Cells
by Elsa Meneses-Salas, Ana García-Melero, Patricia Blanco-Muñoz, Jaimy Jose, Marie-Sophie Brenner, Albert Lu, Francesc Tebar, Thomas Grewal, Carles Rentero and Carlos Enrich
Cells 2020, 9(5), 1152; https://doi.org/10.3390/cells9051152 - 07 May 2020
Cited by 12 | Viewed by 2658
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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18 pages, 4358 KiB  
Article
Exploring Biased Agonism at FPR1 as a Means to Encode Danger Sensing
by Jieny Gröper, Gabriele M. König, Evi Kostenis, Volker Gerke, Carsten A. Raabe and Ursula Rescher
Cells 2020, 9(4), 1054; https://doi.org/10.3390/cells9041054 - 23 Apr 2020
Cited by 7 | Viewed by 4376
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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12 pages, 1648 KiB  
Article
The Essential Role of anxA2 in Langerhans Cell Birbeck Granules Formation
by Shantae M. Thornton, Varsha D. Samararatne, Joseph G. Skeate, Christopher Buser, Kim P. Lühen, Julia R. Taylor, Diane M. Da Silva and W. Martin Kast
Cells 2020, 9(4), 974; https://doi.org/10.3390/cells9040974 - 15 Apr 2020
Cited by 6 | Viewed by 5620
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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15 pages, 3058 KiB  
Article
Annexin A1 Regulates NLRP3 Inflammasome Activation and Modifies Lipid Release Profile in Isolated Peritoneal Macrophages
by José Marcos Sanches, Laura Migliari Branco, Gustavo Henrique Bueno Duarte, Sonia Maria Oliani, Karina Ramalho Bortoluci, Vanessa Moreira and Cristiane Damas Gil
Cells 2020, 9(4), 926; https://doi.org/10.3390/cells9040926 - 09 Apr 2020
Cited by 24 | Viewed by 3542
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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22 pages, 1349 KiB  
Review
Diverse Roles of Annexin A6 in Triple-Negative Breast Cancer Diagnosis, Prognosis and EGFR-Targeted Therapies
by Olga Y. Korolkova, Sarrah E. Widatalla, Stephen D. Williams, Diva S. Whalen, Heather K. Beasley, Josiah Ochieng, Thomas Grewal and Amos M. Sakwe
Cells 2020, 9(8), 1855; https://doi.org/10.3390/cells9081855 - 07 Aug 2020
Cited by 20 | Viewed by 4307
Abstract
The calcium (Ca2+)-dependent membrane-binding Annexin A6 (AnxA6), is a multifunctional, predominantly intracellular scaffolding protein, now known to play relevant roles in different cancer types through diverse, often cell-type-specific mechanisms. AnxA6 is differentially expressed in various stages/subtypes of several cancers, and its [...] Read more.
The calcium (Ca2+)-dependent membrane-binding Annexin A6 (AnxA6), is a multifunctional, predominantly intracellular scaffolding protein, now known to play relevant roles in different cancer types through diverse, often cell-type-specific mechanisms. AnxA6 is differentially expressed in various stages/subtypes of several cancers, and its expression in certain tumor cells is also induced by a variety of pharmacological drugs. Together with the secretion of AnxA6 as a component of extracellular vesicles, this suggests that AnxA6 mediates distinct tumor progression patterns via extracellular and/or intracellular activities. Although it lacks enzymatic activity, some of the AnxA6-mediated functions involving membrane, nucleotide and cholesterol binding as well as the scaffolding of specific proteins or multifactorial protein complexes, suggest its potential utility in the diagnosis, prognosis and therapeutic strategies for various cancers. In breast cancer, the low AnxA6 expression levels in the more aggressive basal-like triple-negative breast cancer (TNBC) subtype correlate with its tumor suppressor activity and the poor overall survival of basal-like TNBC patients. In this review, we highlight the potential tumor suppressor function of AnxA6 in TNBC progression and metastasis, the relevance of AnxA6 in the diagnosis and prognosis of several cancers and discuss the concept of therapy-induced expression of AnxA6 as a novel mechanism for acquired resistance of TNBC to tyrosine kinase inhibitors. Full article
(This article belongs to the Special Issue Recent Developments in Annexin Biology)
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14 pages, 503 KiB  
Review
Annexin A2 in Inflammation and Host Defense
by Valentina Dallacasagrande and Katherine A. Hajjar
Cells 2020, 9(6), 1499; https://doi.org/10.3390/cells9061499 - 19 Jun 2020
Cited by 66 | Viewed by 5659
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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13 pages, 1695 KiB  
Review
Interdisciplinary Synergy to Reveal Mechanisms of Annexin-Mediated Plasma Membrane Shaping and Repair
by Poul Martin Bendix, Adam Cohen Simonsen, Christoffer D. Florentsen, Swantje Christin Häger, Anna Mularski, Ali Asghar Hakami Zanjani, Guillermo Moreno-Pescador, Martin Berg Klenow, Stine Lauritzen Sønder, Helena M. Danielsen, Mohammad Reza Arastoo, Anne Sofie Heitmann, Mayank Prakash Pandey, Frederik Wendelboe Lund, Catarina Dias, Himanshu Khandelia and Jesper Nylandsted
Cells 2020, 9(4), 1029; https://doi.org/10.3390/cells9041029 - 21 Apr 2020
Cited by 27 | Viewed by 5477
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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