Annexin II Enhances Cytomegalovirus Binding and Fusion to Phospholipid Membranes

Abstract

A number of studies have suggested that the anionic phospholipid (anPL)-binding protein annexin II may play a role in cytomegalovirus (CMV) infection. Since annexin II has been shown to mediate aggregation and fusion of certain membranes, we investigated whether these properties could be exploited by CMV directly. The experiments showed that purified annexin II, but not the homologous protein annexin V (AnV), can mediate the binding of 35S-CMV (strain AD169) to anPL-coated microtiter wells. This association required Ca2+, could be titrated by varying either annexin II (apparent Kd = 4 x 10(-)8 M) or 35S-CMV, was inhibited by unlabeled CMV, and was observed for the heterotetrameric or monomeric form of annexin II. In experiments utilizing the fluorescence dequenching of octadecyl rhodamine incorporated into the CMV envelope, annexin II was furthermore found to enhance the rate of virus-anPL vesicle fusion. The observed fusion was dependent on the concentration of annexin II, Ca2+, and anPL and was mediated principally by the heterotetramer. Interestingly, AnV was observed to inhibit the effects of annexin II on CMV fusion but not binding to anPL, which indicates that annexin II enhances these processes by distinct mechanisms. The results presented here provide the first direct evidence that annexin II has the capacity to bridge CMV to a phospholipid membrane and to enhance virus-membrane fusion. These observations furthermore suggest that AnV may regulate the fusogenic function of annexin II.

Thrombin induces endothelial cell-surface exposure of the plasminogen receptor annexin 2

“…Thus, a novel feedback regulatory step in hemostasis is indicated that links thrombin, the biological mediator of coagulation, to enhanced cellular production of the fibrinolytic enzyme, plasmin. Cell-surface A2 has been suggested to have importance in several processes, such as tenascein C-binding (Chung and Erickson, 1994), tumor invasion (Mai et al, 2000) and cytomegalovirus infection (Raynor et al, 1999;Wright et al, 1995). Therefore, the finding that exposure of cell-surface A2 can be induced by thrombin might have implications in areas additional to fibrinolysis.…”

Emerging functions as host cell factors – an encyclopedia of annexin-pathogen interactions

“…Interestingly, small molecule inhibitors of the AnxA2/S100A10 complex substantially reduced HPV16 infection in a cell culture model (Woodham et al, 2015). AnxA2 was reported to interact with HCMV glycoprotein B (Bold et al, 1996;Pietropaolo and Compton, 1997), and, together with S100A10, to facilitate CMV infection (Derry et al, 2007) probably through enhanced fusion of the virus with the host cell (Raynor et al, 1999). However, this was not confirmed in another study (Pietropaolo and Compton, 1999).…”

“…AnxA5 is associated with herpes simplex virus (HSV) type 1 (Loret et al, 2008), HIV-1 (Chertova et al, 2006), VSV (Moerdyk-Schauwecker et al, 2009, Rift Valley fever virus (Nuss et al, 2014), and IAV (Shaw et al, 2008). How and at which stage in the virus infection cycle annexins are acquired remains so far unclear (which Gershom et al, 2012Wright et al, 1994Wright et al, 1995;Pietropaolo and Compton 1997;Pietropaolo and Compton 1999;Raynor et al, 1999;Varnum et al, 2004;Derry et al, 2007 generally holds true for virus-embedded host cell proteins), and the association might simply reflect the nature of the specialized membrane domains where viral assembly and budding take place. Viruses that bud from lipidenriched plasma membrane domains ('rafts') would then incorporate the often raft-associated annexins as part of their host cell membrane-derived viral envelope.…”

IL-13, Asthma and Glycosylation in Airway Epithelial Repair

“…As a cell surface molecule, it has been suggested that AII is the human cytomegalovirus receptor [105]. Following the initial interaction with heparan sulfate proteoglycan, the virus particle is primed for membrane fusion and infection [106,107].…”

“…Increased tyrosine phosphorylation of the EGFR has also been observed after mechanical injury even in the absence of exogenous ligand [24]. While a critical role of signaling mediated by EGFR in repairing damaged epithelium has been well demonstrated in many epithelial systems, an important role for core glycosylation of extracellular domain of EGFR in ligand binding and tyrosine kinase activity has also been documented [105][106][107]. The extracellular domain of EGFR has 10 to 11 potential site for N-glycosylation.…”