Astrocytic αVβ3 Integrin Inhibits Neurite Outgrowth and Promotes Retraction of Neuronal Processes by Clustering Thy-1

Herrera-Molina, Rodrigo; Frischknecht, Renato; Maldonado, Horacio; Seidenbecher, Constanze I.; Gundelfinger, Eckart D.; Hetz, Claudio; Aylwin, María de la Luz; Schneider, Pascal; Quest, Andrew F. G.; Leyton, Lisette

doi:10.1371/journal.pone.0034295

Cited by 59 publications

(73 citation statements)

References 51 publications

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“…We also found that blocking THY-1 inhibited virus-induced activation of PI3K/Akt. THY-1 is known to interact with integrins (47)(48)(49)(50) and is a major protein present in clathrin-independent endocytic vesicles (39). Since macropinocytosis is PI3K/Akt dependent, involves integrin signaling, and is a clathrin-independent endocytic process, we determined whether THY-1 has a role in HCMV entry by macropinocytosis.…”

Section: Resultsmentioning

confidence: 99%

Cell Surface THY-1 Contributes to Human Cytomegalovirus Entry via a Macropinocytosis-Like Process

Fischer

Cohen

2016

J Virol

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Previously we showed that THY-1 has a critical role in the initial stage of infection of certain cell types with human cytomegalovirus (HCMV) and that THY-1 is important for HCMV-mediated activation of phosphatidylinositol 3-kinase (PI3K)/Akt during virus entry. THY-1 is known to interact with integrins and is a major cargo protein of clathrin-independent endocytic vesicles. Since macropinocytosis involves integrin signaling, is PI3K/Akt dependent, and is a clathrin-independent endocytic process, we determined whether THY-1 has a role in HCMV entry by macropinocytosis. Using electron microscopy in two cell lines that support HCMV infection in a THY-1-dependent manner, we found that HCMV enters these cells by a macropinocytosis-like process. THY-1 associated with HCMV virions on the cell surface and colocalized with virus inside macropinosomes. 5-(N-Ethyl-Nisopropyl)amiloride (EIPA) and soluble THY-1 blocked HCMV infection in the cell lines by >80% and 60%, respectively. HCMV entry into the cells triggered increased influx of extracellular fluid, a marker of macropinocytosis, and this increased fluid uptake was inhibited by EIPA and by soluble THY-1. Blocking actin depolymerization, Na ؉ /H ؉ exchange, PI3K, and Pak1 kinase, which are critical for macropinocytosis, impaired HCMV infection. Neither internalized HCMV virions nor THY-1 in virus-infected cells colocalized with transferrin as determined by confocal microscopy, indicating that clathrin-mediated endocytosis was not involved in THY-1-associated virus entry. These results suggest that HCMV has adapted to utilize THY-1, a cargo protein of clathrin-independent endocytotic vesicles, to facilitate efficient entry into certain cell types by a macropinocytosis-like process. IMPORTANCE Human cytomegalovirus (HCMV) infects over half of the population and is the most common infectious cause of birth defects.The virus is the most important infection occurring in transplant recipients. The mechanism of how HCMV enters cells is controversial. In this study, we show that THY-1, a cell surface protein that is critical for the early stage of entry of HCMV into certain cell types, contributes to virus entry by macropinocytosis. Our findings suggest that HCMV has adapted to utilize THY-1 to facilitate entry of HCMV into macropinosomes in certain cell types. Further knowledge about the mechanism of HCMV entry into cells may facilitate the development of novel inhibitors of virus infection. Human cytomegalovirus (HCMV) infects over half of the general population. While the infection is often asymptomatic when occurring in young children, it poses a serious health threat in transplant recipients and in immunocompromised individuals. HCMV is the most common infectious cause of birth defects. The virus infects a variety of host cells in vivo, including epithelial, endothelial, and muscle cells as well as fibroblasts. HCMV encodes multiple glycoproteins, some of which are not shared with other human herpesviruses, such as UL128, UL130, and UL131A. Other glycoproteins ar...

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Section: Resultsmentioning

confidence: 99%

Cell Surface THY-1 Contributes to Human Cytomegalovirus Entry via a Macropinocytosis-Like Process

Fischer

Cohen

2016

J Virol

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“…An α v β 3 integrin has been reported to bind to Thy-1 and trigger clustering of Thy-1, inactivation of Src, and neurite outgrowth inhibition (Herrera-Molina et al 2012 ). The complete fl ow of signaling events initiated as a consequence of Thy-1 integrin interactions awaits further investigation.…”

Section: Role Of Thy-1 In Neurobiologymentioning

confidence: 99%

“…Indeed, recently published studies reported that the α v β 3 integrin serves as a ligand for Thy-1 in neurons, which upon binding induces Thy-1 to aggregate in the plasma membrane and leads to neurite outgrowth inhibition and retraction of already formed processes (Herrera-Molina et al 2012 ). Astrocytes expressing α v β 3 , but not those in which the β 3 subunit has been reduced by specifi c siRNA, inhibit neurite growth of primary cortical neurons maintained for 4-7 days in culture.…”

Section: Neuronal Thy-1 and Its Interactions With Astrocytesmentioning

confidence: 99%

Thy-1 Modulates Neurological Cell–Cell and Cell–Matrix Interactions Through Multiple Molecular Interactions

Leyton

Hagood

2013

Advances in Neurobiology

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Thy-1, or CD90, is a glycosylphosphatidylinositol-linked cell surface glycoprotein expressed on multiple cell types, including neurons, thymocytes, fi broblasts, endothelial cells, mesangial cells, and some hematopoietic and stromal stem cells. Thy-1 is developmentally regulated and evolutionarily conserved. Its cellular effects vary between and in some cases within cell types, tissues, and species, indicating that its biological role is context dependent. However, it most often seems to affect cell-cell or cell-matrix interactions and cellular adhesion and migration. In the nervous system, Thy-1 mediates bidirectional cell-cell communication, which modulates cell-matrix adhesion. Neurons express high levels of Thy-1, which interacts with α v β 3 integrin present in astrocytes and stimulates increased astrocyte adhesion to the underlying surface ( trans signaling) and in neurites, the same ligand-receptor association triggers neurite retraction and inhibition of axonal growth ( cis signaling). Although Thy-1 lacks a cytoplasmic domain, it affects multiple intracellular signaling cascades through interaction with a number of molecules within lipid raft microdomains. Improved understanding of how this enigmatic adhesion molecule modulates signaling and cell phenotype may yield novel insights into neurodevelopment and nerve recovery after injury.

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“…Integrin binding to neuronal Thy-1 results in the activation of astrocytes. In turn, the astrocyte integrin induces clustering of neuronal Thy-1, thereby leading to the inhibition of neurite outgrowth and to the retraction of neuronal processes [81]. This bi-directional astrocyte-neuron communication via integrins might play an important role in the process of axon repair following neuronal damage.…”

Section: Integrins In the Central Nervous Systemmentioning

confidence: 99%

Integrins and Nitric Oxide in the Regulation of Glial Cells: Potential Roles in Pathological Pain

Okamoto¹,

Shimaoka²

2013

J Anesthe Clinic Res

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Glial cells form physical connections with neurons and vascular endothelial cells in the brain, thereby constructing the elaborate networks of the tripartite synapse and the neurovascular unit, respectively. In addition to supporting neurons, glial cells modify synaptic plasticity and vascular tone, and in this way play an important role in maintaining brain homeostasis. Upon activation, glial cells produce nitric oxide, a gaseous mediator that diffuses into neighboring cells, wherein it elicits signaling pathways critical for synaptic plasticity and vascular tone. Because nitric oxide is short-lived and can travel only a short distance, glial cells must migrate to and position themselves near the target cells with which glial nitric oxide primarily interacts. Integrins, an essential family of cell adhesion molecules, facilitate effective glial migration and adhesion in the brain during developmental and normal adult stages. Aberrant regulation of nitric oxide and integrins in glial cells is thought to compromise cognitive brain function, and thereby lead to various pathologies. This review focuses on the important pathologic roles that nitric oxide and integrins play in glia and glia-related cells, focusing on their potential involvement in chronic pain syndrome.

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Astrocytic αVβ3 Integrin Inhibits Neurite Outgrowth and Promotes Retraction of Neuronal Processes by Clustering Thy-1

Cited by 59 publications

References 51 publications

Cell Surface THY-1 Contributes to Human Cytomegalovirus Entry via a Macropinocytosis-Like Process

Cell Surface THY-1 Contributes to Human Cytomegalovirus Entry via a Macropinocytosis-Like Process

Thy-1 Modulates Neurological Cell–Cell and Cell–Matrix Interactions Through Multiple Molecular Interactions

Integrins and Nitric Oxide in the Regulation of Glial Cells: Potential Roles in Pathological Pain

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