Axl Can Serve as Entry Factor for Lassa Virus Depending on the Functional Glycosylation of Dystroglycan

Fedeli, Chiara; Torriani, Giulia; Galan-Navarro, Clara; Moraz, Marie-Laurence; Moreno, Hector; Gerold, Gisa; Kunz, Stefan

doi:10.1128/jvi.01613-17

Cited by 64 publications

(74 citation statements)

References 103 publications

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“…In this study, we found that that PtdSer receptor TIM-1 mediates the entry of either LCMV or vesicular stomatitis virus (VSV) pseudovirions bearing LASV GP but only when ␣DG either is not expressed or does not contain the necessary LARGE-dependent alterations of the O-linked glycans. This is consistent with findings that the high-affinity interactions of LASV GP and ␣DG prevail over lower-affinity PtdSer/PtdSer receptor interactions (49). Furthermore, we found that the TAM receptor Axl was unable to serve as a receptor for LASV pseudovirions in HEK 293T and Vero cells, irrespective of the status of ␣DG in these cells.…”

Section: Importancesupporting

confidence: 92%

TIM-1 Mediates Dystroglycan-Independent Entry of Lassa Virus

Brouillette

Phillips

Patel

et al. 2018

J Virol

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Lassa virus (LASV) is an Old World arenavirus responsible for hundreds of thousands of infections in West Africa every year. LASV entry into a variety of cell types is mediated by interactions with glycosyltransferase LARGE-modified O-linked glycans present on the ubiquitous receptor α-dystroglycan (αDG). However, cells lacking αDG are permissive to LASV infection, suggesting that alternative receptors exist. Previous studies demonstrated that the phosphatidylserine (PtdSer)-binding receptors Axl and Tyro3 along with C-type lectin receptors mediate αDG-independent entry. Here, we demonstrate that another PtdSer receptor, TIM-1, mediates LASV glycoprotein (GP)-pseudotyped virion entry into αDG-knocked-out HEK 293T and wild-type (WT) Vero cells, which express αDG lacking appropriate glycosylation. To investigate the mechanism by which TIM-1 mediates enhancement of entry, we demonstrate that mutagenesis of the TIM-1 IgV domain PtdSer-binding pocket abrogated transduction. Furthermore, the human TIM-1 IgV domain-binding monoclonal antibody ARD5 blocked transduction of pseudovirions bearing LASV GP in a dose-dependent manner. Finally, as we showed previously for other viruses that use TIM-1 for entry, a chimeric TIM-1 protein that substitutes the proline-rich region (PRR) from murine leukemia virus envelope (Env) for the mucin-like domain served as a competent receptor. These studies provide evidence that, in the absence of a functional αDG, TIM-1 mediates the entry of LASV pseudoviral particles through interactions of virions with the IgV PtdSer-binding pocket of TIM-1. PtdSer receptors, such as TIM-1, are emerging as critical entry factors for many enveloped viruses. Most recently, hepatitis C virus and Zika virus have been added to a growing list. PtdSer receptors engage with enveloped viruses through the binding of PtdSer embedded in the viral envelope, defining them as GP-independent receptors. This GP-independent entry mechanism should effectively mediate the entry of all enveloped viruses, yet LASV GP-pseudotyped viruses were previously found to be unresponsive to PtdSer receptor enhancement in HEK 293T cells. Here, we demonstrate that LASV pseudovirions can utilize the PtdSer receptor TIM-1 but only in the absence of appropriately glycosylated α-dystroglycan (αDG), the high-affinity cell surface receptor for LASV. Our studies shed light on LASV receptor utilization and explain why previous studies performed with α-DG-expressing cells did not find that LASV pseudovirions utilize PtdSer receptors for virus uptake.

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Section: Importancesupporting

confidence: 92%

TIM-1 Mediates Dystroglycan-Independent Entry of Lassa Virus

Brouillette

Phillips

Patel

et al. 2018

J Virol

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“…Here, we discovered that by inducing actin remodeling GAS6 stimulation triggers macropinosome formation, and GAS6-AXL complexes localize to macropinosomes indicating that a fraction of AXL is internalized via macropinocytosis. Thus, our data provide a mechanistic explanation for previous virology studies reporting that AXL might contribute to macropinocytic uptake of Lassa and Ebola viruses upon infection (Fedeli et al, 2018;Hunt et al, 2011).…”

Section: Discussionsupporting

confidence: 69%

GAS6-AXL signaling triggers actin remodeling and macropinocytosis that drive cancer cell invasion

Zdżalik-Bielecka

Poświata

Kozik

et al. 2020

Preprint

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AXL, a member of the TAM (TYRO3, AXL, MER) receptor tyrosine kinase family, and its ligand GAS6 are implicated in oncogenesis and metastasis of many cancer types. However, the exact cellular processes activated by GAS6-AXL remain largely unexplored. Here, we identified an interactome of AXL and revealed its associations with proteins regulating actin dynamics. Consistently, GAS6-mediated AXL activation triggered actin remodeling manifested by peripheral membrane ruffling and circular dorsal ruffles (CDRs). This further promoted macropinocytosis that mediated the internalization of GAS6-AXL complexes and sustained survival of glioblastoma cells grown under glutamine-deprived conditions. GAS6induced CDRs contributed to focal adhesion (FA) turnover, cell spreading and elongation.Consequently, AXL activation by GAS6 drove invasion of cancer cells in a spheroid model.All these processes required the kinase activity of AXL but not TYRO3, and downstream activation of PI3K. We propose that GAS6-AXL signaling induces multiple actin-driven cytoskeletal rearrangements and macropinocytosis that jointly contribute to cancer cell invasion.

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“…The conserved and widely expressed receptor for extracellular matrix proteins, α-dystroglycan (α-DG), is a main receptor for Old World (OW) mammarenaviruses, such as lymphocytic choriomeningitis virus (LCMV) and Lassa virus (LASV) [38]. Secondary alternative receptors, including members of the Tyro3/Axl/Mer and T-cell immunoglobulin mucin (TIM) receptor families may account for LASV and LCMV infection of cells lacking fully glycosylated α-DG [44,45]. Cell entry of the OW hemorrhagic fever (HF) mammarenavirus Lujo virus (LUJV) is mediated by neuropilin (NRP)-2, a cell-surface receptor for semaphorins [46].…”

mentioning

confidence: 99%

Differences in Tissue and Species Tropism of Reptarenavirus Species Studied by Vesicular Stomatitis Virus Pseudotypes

Korzyukov

Iheozor-Ejiofor

Levanov

et al. 2020

Viruses

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Reptarenaviruses cause Boid Inclusion Body Disease (BIBD), and co-infections by several reptarenaviruses are common in affected snakes. Reptarenaviruses have only been found in captive snakes, and their reservoir hosts remain unknown. In affected animals, reptarenaviruses appear to replicate in most cell types, but their complete host range, as well as tissue and cell tropism are unknown. As with other enveloped viruses, the glycoproteins (GPs) present on the virion's surface mediate reptarenavirus cell entry, and therefore, the GPs play a critical role in the virus cell and tissue tropism. Herein, we employed single cycle replication, GP deficient, recombinant vesicular stomatitis virus (VSV) expressing the enhanced green fluorescent protein (scrVSV∆G-eGFP) pseudotyped with different reptarenavirus GPs to study the virus cell tropism. We found that scrVSV∆G-eGFPs pseudotyped with reptarenavirus GPs readily entered mammalian cell lines, and some mammalian cell lines exhibited higher, compared to snake cell lines, susceptibility to reptarenavirus GP-mediated infection. Mammarenavirus GPs used as controls also mediated efficient entry into several snake cell lines. Our results confirm an important role of the virus surface GP in reptarenavirus cell tropism and that mamma-and reptarenaviruses exhibit high cross-species transmission potential.Viruses 2020, 12, 395 2 of 16 Boid Inclusion Body Disease (BIBD), initially recognized in the 1970s, affects mainly captive boas and pythons [11]. BIBD is characterized by the formation of electron dense intracytoplasmic inclusion bodies (IB) [12] in various cell types (including blood cells) and tissues [13][14][15]. BIBD spreads efficiently within collections, and the recommendation to euthanize snakes with BIBD can lead to loss of entire collections [11]. Clinical manifestations of BIBD are variable and include central nervous system (CNS) signs such as head tremors, loss of coordination, and regurgitation [11]. Death due to secondary bacterial, fungal or protozoal infections and neoplastic diseases is common in snakes with BIBD [16], suggesting that BIBD might be associated with an impaired immune response.The causative agent for BIBD remained unknown until the early 2010s, when novel arenaviruses were identified in snakes with BIBD [13,15,17], which extended arenaviruses host range to species other than the well-established rodent reservoirs [1-3]. These findings led to establishment of two genera, Mammarenavirus and Reptarenavirus, within the family Arenaviridae [18,19]. We and others have documented that snakes with BIBD are often co-infected with several reptarenaviruses [20,21], and we discovered another novel arenavirus in snakes, Haartman Institute Snake virus-1 (HISV-1) [20], which later became the type species of a third arenavirus genus, Hartmanivirus [19,22]. The finding that IBs contain reptarenavirus NP further supported the link between reptarenavirus infection and BIBD [15]. Experimental infection of boas and pythons with purified reptarenaviruses provided une...

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Axl Can Serve as Entry Factor for Lassa Virus Depending on the Functional Glycosylation of Dystroglycan

Cited by 64 publications

References 103 publications

TIM-1 Mediates Dystroglycan-Independent Entry of Lassa Virus

TIM-1 Mediates Dystroglycan-Independent Entry of Lassa Virus

GAS6-AXL signaling triggers actin remodeling and macropinocytosis that drive cancer cell invasion

Differences in Tissue and Species Tropism of Reptarenavirus Species Studied by Vesicular Stomatitis Virus Pseudotypes

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