The Ca2+- and phospholipid-binding protein Annexin A2 is able to increase and decrease plasma membrane order

ABSTRACTBackgroundAnnexin A2 is a phospholipid-binding protein involved in fibrinolysis, cell membrane stabilization and repair, and ensuring the integrity of the pulmonary microvasculature. Given the autoantibodies observed in COVID-19 and that Annexin A2 is a known target of antiphospholipid antibodies, we studied autoimmunity directed against Annexin A2 among hospitalized COVID-19 patients.MethodsWe used ELISA to identify the levels of IgG autoantibodies recognizing Annexin A2 and A5 among 86 hospitalized cases of COVID-19. Using logistic regression, we analyzed the association between anti-Annexin A2 and A5 antibody levels with mortality after adjusting for age, sex, race and key comorbidities.ResultsWe found higher average levels of anti-Annexin A2 antibodies among hospitalized COVID-19 patients that died when compared with non-critical hospitalized COVID-19 patients (p-value = 0.006) and critically ill COVID-19 patients (p-value = 0.04). No significant differences in anti-Annexin A5 antibody levels were identified. Regression analysis showed that anti-Annexin A2 antibody levels as measured in relative units strongly predicted mortality with an odds ratio of 9.3 (95% CI: 1.9 to 44.6, p=0.005). In contrast, anti-Annexin A5 antibody levels were not associated with higher mortality (95% CI: 0.5 to 15.2, p=0.22).ConclusionsWe determined that anti-Annexin A2 antibodies were elevated among hospitalized COVID-19 patients and these levels predicted mortality. It is known that inhibition of Annexin A2 induces systemic thrombosis, cell death, and non-cardiogenic pulmonary edema. Autoimmunity to Annexin A2 is a potential mechanism that may explain the key clinical findings of severe COVID-19.

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Purification, crystallization, and preliminary X-ray diffraction analysis of rat kidney annexin V, a calcium-dependent phospholipid-binding protein.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)39600-0 ◽

1990 ◽

Vol 265 (8) ◽

pp. 4567-4569

Author(s):

B A Seaton ◽

J F Head ◽

M A Kaetzel ◽

J R Dedman

Keyword(s):

Diffraction Analysis ◽

Binding Protein ◽

Rat Kidney ◽

Annexin V ◽

X Ray Diffraction ◽

X Ray ◽

Phospholipid Binding ◽

Calcium Dependent

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Redistribution of a rab3-like GTP-binding protein from secretory granules to the Golgi complex in pancreatic acinar cells during regulated exocytosis

The Journal of Cell Biology ◽

10.1083/jcb.124.1.43 ◽

1994 ◽

Vol 124 (1) ◽

pp. 43-53 ◽

Cited By ~ 54

Author(s):

BP Jena ◽

FD Gumkowski ◽

EM Konieczko ◽

GF von Mollard ◽

R Jahn ◽

...

Keyword(s):

Plasma Membrane ◽

Golgi Complex ◽

Binding Protein ◽

Secretory Granules ◽

Acinar Cells ◽

Pancreatic Acinar Cells ◽

Apical Plasma Membrane ◽

Gtp Binding Protein ◽

Regulated Exocytosis ◽

Gtp Binding

Regulated secretion from pancreatic acinar cells occurs by exocytosis of zymogen granules (ZG) at the apical plasmalemma. ZGs originate from the TGN and undergo prolonged maturation and condensation. After exocytosis, the zymogen granule membrane (ZGM) is retrieved from the plasma membrane and ultimately reaches the TGN. In this study, we analyzed the fate of a low M(r) GTP-binding protein during induced exocytosis and membrane retrieval using immunoblots as well as light and electron microscopic immunocytochemistry. This 27-kD protein, identified by a monoclonal antibody that recognizes rab3A and B, may be a novel rab3 isoform. In resting acinar cells, the rab3-like protein was detected primarily on the cytoplasmic face of ZGs, with little labeling of the Golgi complex and no significant labeling of the apical plasmalemma or any other intracellular membranes. Stimulation of pancreatic lobules in vitro by carbamylcholine for 15 min, resulted in massive exocytosis that led to a near doubling of the area of the apical plasma membrane. However, no relocation of the rab3-like protein to the apical plasmalemma was seen. After 3 h of induced exocytosis, during which time approximately 90% of the ZGs is released, the rab3-like protein appeared to translocate to small vesicles and newly forming secretory granules in the TGN. No significant increase of the rab3-like protein was found in the cytosolic fraction at any time during stimulation. Since the protein is not detected on the apical plasmalemma after stimulation, we conclude that recycling may involve a membrane dissociation-association cycle that accompanies regulated exocytosis.

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Purification of a cortisol binding protein from hepatic plasma membrane

Biochimica et Biophysica Acta (BBA) - Biomembranes ◽

10.1016/0005-2736(96)00110-1 ◽

1996 ◽

Vol 1284 (1) ◽

pp. 41-46 ◽

Cited By ~ 13

Author(s):

Iñaki Ibarrola ◽

Miriam Andrés ◽

Aída Marino ◽

JoséM. Macarulla ◽

Miguel Trueba

Keyword(s):

Plasma Membrane ◽

Binding Protein

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The Ca2+-binding protein PCaP2 located on the plasma membrane is involved in root hair development as a possible signal transducer

The Plant Journal ◽

10.1111/tpj.12155 ◽

2013 ◽

Vol 74 (4) ◽

pp. 690-700 ◽

Cited By ~ 23

Author(s):

Mariko Kato ◽

Takashi Aoyama ◽

Masayoshi Maeshima

Keyword(s):

Plasma Membrane ◽

Root Hair ◽

Binding Protein ◽

Signal Transducer ◽

Root Hair Development ◽

Hair Development

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Munc13-4 Is a Rab11-binding Protein That Regulates Rab11-positive Vesicle Trafficking and Docking at the Plasma Membrane

Journal of Biological Chemistry ◽

10.1074/jbc.m115.705871 ◽

2015 ◽

Vol 291 (7) ◽

pp. 3423-3438 ◽

Cited By ~ 36

Author(s):

Jennifer L. Johnson ◽

Jing He ◽

Mahalakshmi Ramadass ◽

Kersi Pestonjamasp ◽

William B. Kiosses ◽

...

Keyword(s):

Plasma Membrane ◽

Binding Protein ◽

Vesicle Trafficking

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Developmentally regulated expression of insulin-like growth factors by differentiated murine teratocarcinomas and extraembryonic mesoderm

Development ◽

10.1242/dev.95.1.193 ◽

1986 ◽

Vol 95 (1) ◽

pp. 193-212

Author(s):

John K. Heath ◽

Wai-Kang Shi

Keyword(s):

Plasma Membrane ◽

Binding Protein ◽

Membrane Receptors ◽

Developmentally Regulated ◽

Igf Receptors ◽

Igf Binding ◽

Plasma Membrane Receptors ◽

Igf Binding Protein ◽

Culture Supernatants ◽

Insulin Like Growth Factors

The expression of plasma membrane receptors for insulin-like growth factors (IGFs) by PC13 embryonal carcinoma (EC) cells, and their immediate differentiated progeny PC13END was examined by binding radiolabelled IGF-I to cell monolayers. Both cell types express high-affinity IGF receptors, but the apparent number of unoccupied receptor sites falls by about 60% upon differentiation. Crosslinking studies reveal that both type 1 and type 2 IGF receptors are expressed by PC13EC cells. PC13END-cell-conditioned medium contains developmentally regulated, separable activities, one of which reacts directly with IGF-II, and the other with IGF for plasma membrane receptors. The former activity represents a soluble secreted IGF-binding protein. The latter activity is structurally and functionally similar to rat IGF-II. Polyclonal antibodies raised against purified rat IGF-II specifically recognize multiple forms of IGF in radiolabelled culture supernatants and material which closely resembles the soluble IGF-binding protein. Immunoprecipitation of radiolabelled culture supernatants with anti-rat IGF-II reveals that the differentiation of PC13EC cells is accompanied by the coexpression of IGF-like molecules and the soluble binding protein, and that IGF-like molecules are expressed by extraembryonic tissues of mesodermal origin in the early postimplantation mouse embryo. These findings show that IGF-like molecules are expressed in early mammalian development and may act in an autocrine fashion in vivo.

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