Annexin A5 inhibits engulfment through internalization of PS-expressing cell membrane patches

Kenis, Heidi; Genderen, Hugo van; Deckers, Niko; Lux, Petra; Hofstra, Leo; Narula, Jagat; Reutelingsperger, Chris

doi:10.1016/j.yexcr.2005.11.023

Cited by 55 publications

(57 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…ANX V has been used to occlude PtdSer on dead cells and block binding to MFG-E8 (19) or phagocytosis of apoptotic cells (81); however, ANX V cannot block viral entry via MFG-E8 and TIM-1 and -4. On the other hand, we found that a mutant of MFG-E8, D89E, can block MFG-E8-, TIM-1-, and TIM-4-mediated lentiviral transduction.…”

Section: Discussionmentioning

confidence: 99%

Role of Phosphatidylserine Receptors in Enveloped Virus Infection

Morizono

Chen

2014

J Virol

159

178

View full text Add to dashboard Cite

We recently demonstrated that a soluble protein, Gas6, can facilitate viral entry by bridging viral envelope phosphatidylserine to Axl, a receptor tyrosine kinase expressed on target cells. The interaction between phosphatidylserine, Gas6, and Axl was originally shown to be a molecular mechanism through which phagocytes recognize phosphatidylserine exposed on dead cells. Since our initial report, several groups have confirmed that Axl/Gas6, as well as other phosphatidylserine receptors, facilitate entry of dengue, West Nile, and Ebola viruses. Virus binding by viral envelope phosphatidylserine is now a viral entry mechanism generalized to many families of viruses. In addition to Axl/Gas6, various molecules are known to recognize phosphatidylserine; however, the effects of these molecules on virus binding and entry have not been comprehensively evaluated and compared. In this study, we examined most of the known human phosphatidylserine-recognizing molecules, including MFG-E8, TIM-1, -3, and -4, CD300a, BAI1, and stabilin-1 and -2, for their abilities to facilitate virus binding and infection. Using pseudotyped lentiviral vectors, we found that a soluble phosphatidylserine-binding protein, MFG-E8, enhances transduction. Cell surface receptors TIM-1 and -4 also enhance virus binding/transduction. The extent of enhancement by these molecules varies, depending on the type of pseudotyping envelope proteins. Mutated MFG-E8, which binds viral envelope phosphatidylserine without bridging virus to cells, but, surprisingly, not annexin V, which has been used to block phagocytosis of dead cells by concealing phosphatidylserine, efficiently blocks these phosphatidylserine-dependent viral entry mechanisms. These results provide insight into understanding the role of viral envelope phosphatidylserine in viral infection. IMPORTANCEEnvelope phosphatidylserine has previously been shown to be important for replication of various envelope viruses, but details of this mechanism(s) were unclear. We were the first to report that a bifunctional serum protein, Gas6, bridges envelope phosphatidylserine to a cell surface receptor, Axl. Recent studies demonstrated that many envelope viruses, including vaccinia, dengue, West Nile, and Ebola viruses, utilize Axl/Gas6 to facilitate their entry, suggesting that the phosphatidylserine-mediated viral entry mechanism can be shared by various enveloped viruses. In addition to Axl/Gas6, various molecules are known to recognize phosphatidylserine; however, the effects of these molecules on virus binding and entry have not been comprehensively evaluated and compared. In this study, we examined most human phosphatidylserine-recognizing molecules for their abilities to facilitate viral infection. The results provide insights into the role(s) of envelope phosphatidylserine in viral infection, which can be applicable to the development of novel antiviral reagents that block phosphatidylserine-mediated viral entry.

show abstract

Section: Discussionmentioning

confidence: 99%

Role of Phosphatidylserine Receptors in Enveloped Virus Infection

Morizono

Chen

2014

J Virol

159

178

View full text Add to dashboard Cite

show abstract

“…RGD-anxA5 stimulated efferocytosis by THP-1 macrophages with 40%, whereas RGT-anxA5 inhibited it with 33% ( Figure 3a) and lactadherin stimulates efferocytosis with 60% (data not shown) as measured with a recently described efferocytosis assay (Supplementary Figures S2A and B). 13 This 40% stimulation can completely Figure 1 (a) The ribbon structure is given for human anxA5, colored from N to C terminus following blue-to-red standard coloring. The wild-type sequence from human anxA5 (PDB accession number 1anw.pdb) was mutated in silico by the introduction of a Thr8Asp missense mutation after which the structure was regularized and minimized using the ICM Promolecular modeling package (Molsoft LLC).…”

Section: Integrin-binding In Vitromentioning

confidence: 99%

“…10 AnxA5 does not act as a bridging molecule but inhibits efferocytosis by shielding the PS-expressing surface of apoptotic cells. 12,13 The molecular imaging experience with anxA5 triggered us to explore whether anxA5 could be transformed into a therapeutic agent enhancing efferocytosis. It has been shown that the PS receptor TIM-4 (T-cell immunoglobulin-and mucin-domain-containing molecule-4) and integrin a v b 3/5 act cooperatively during efferocytosis.…”

mentioning

confidence: 99%

Cell surface-expressed phosphatidylserine as therapeutic target to enhance phagocytosis of apoptotic cells

et al. 2012

View full text Add to dashboard Cite

Impaired efferocytosis has been shown to be associated with, and even to contribute to progression of, chronic inflammatory diseases such as atherosclerosis. Enhancing efferocytosis has been proposed as strategy to treat diseases involving inflammation. Here we present the strategy to increase 'eat me' signals on the surface of apoptotic cells by targeting cell surfaceexpressed phosphatidylserine (PS) with a variant of annexin A5 (Arg-Gly-Asp-annexin A5, RGD-anxA5) that has gained the function to interact with a v b 3 receptors of the phagocyte. We describe design and characterization of RGD-anxA5 and show that introduction of RGD transforms anxA5 from an inhibitor into a stimulator of efferocytosis. RGD-anxA5 enhances engulfment of apoptotic cells by phorbol-12-myristate-13-acetate-stimulated THP-1 (human acute monocytic leukemia cell line) cells in vitro and resident peritoneal mouse macrophages in vivo. In addition, RGD-anxA5 augments secretion of interleukin-10 during efferocytosis in vivo, thereby possibly adding to an anti-inflammatory environment. We conclude that targeting cell surfaceexpressed PS is an attractive strategy for treatment of inflammatory diseases and that the rationally designed RGD-anxA5 is a promising therapeutic agent.

show abstract

“…Annexin-V not only inhibits phagocytosis by shielding PS, but also by interfering with PS-associated receptors and ligands. 86 Recently, Jinushi et al 87 proposed a novel immunoregulatory effect of MFG-E8-mediated uptake of apoptotic cells. MFG-E8 is a bridging molecule that stimulates phagocytosis of apoptotic cells through specific binding to PS on apoptotic cells via COOH-terminal factor VIII homologous domain and to avb3 integrin expressed on phagocytes via an NH 2 -terminal EGF-like domain.…”

Section: Exploitation Of Molecules On the Surface Of Dying Cells For mentioning

confidence: 99%

From regulation of dying cell engulfment to development of anti-cancer therapy

Krysko

Vandenabeele

2007

Cell Death Differ

View full text Add to dashboard Cite

Cell death and efficient engulfment of dying cells ensure tissue homeostasis and is involved in pathogenesis. Clearance of dying cells is a complex and dynamic process coordinated by interplay between ligands on dying cell, bridging molecules, and receptors on engulfing cells. In this review, we will discuss recent advances and significance of molecular changes on the surface of dying cells implicated in their recognition and clearance as well as factors released by dying cells that attract macrophages to the site of cell death. It is now becoming apparent that phagocytes use a specific set of mechanisms to discriminate between live and dead cells, and this phenomenon will be illustrated here. Next, we will discuss potential mechanisms by which removal of dying cells could modulate immune responses of phagocytes, in particular of macrophages. Finally, we will address possible strategies for manipulating the immunogenicity of dying cells in experimental cancer therapies.

show abstract

Annexin A5 inhibits engulfment through internalization of PS-expressing cell membrane patches

Cited by 55 publications

References 42 publications

Role of Phosphatidylserine Receptors in Enveloped Virus Infection

Role of Phosphatidylserine Receptors in Enveloped Virus Infection

Cell surface-expressed phosphatidylserine as therapeutic target to enhance phagocytosis of apoptotic cells

From regulation of dying cell engulfment to development of anti-cancer therapy

Contact Info

Product

Resources

About