Posttranslational Modification of α-Dystroglycan, the Cellular Receptor for Arenaviruses, by the Glycosyltransferase LARGE Is Critical for Virus Binding

Kunz, Stefan; Rojek, Jillian M.; Kanagawa, Motoi; Spiropoulou, Christina F.; Barresi, Rita; Campbell, Kevin P.; Oldstone, Michael B. A.

doi:10.1128/jvi.79.22.14282-14296.2005

Cited by 139 publications

(189 citation statements)

References 63 publications

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“…Cl13 infected 62% of lung vascular endothelial cells compared with <1% infected by ARM (Fig. 4D), consistent with the binding of Cl13 to α-DG, highly expressed by these cells (7,9,11,38). IFNAR antibody treatment did not inhibit, but rather enhanced, endothelial cell infection, likely due to the absence of antiviral effects mediated by IFN-I signaling (Fig.…”

Section: Ifn-i Signaling On Nonhematopoietic Cells Is Critical For Pasupporting

confidence: 56%

“…Like LASV, LCMV is an Old World arenavirus and serves as the prototype virus for this subgroup of the Arenaviridae family. Studies on LCMV have provided critical insights into Old World arenavirus virology, immunity, and pathogenesis, and led to the discovery of α-dystroglycan (α-DG), posttranslationally modified by the glycosyltransferase LARGE, as the cognate cellular receptor for both LCMV and LASV (7)(8)(9)(10).…”

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confidence: 99%

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Type I interferon is a therapeutic target for virus-induced lethal vascular damage

Baccalà¹,

Welch²,

Gonzalez-Quintial³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Lassa virus is, after dengue virus, the second most common cause of viral hemorrhagic fever. In susceptible individuals, Lassa virus infection is associated with vascular permeability, leading to tissue edema, organ failure, and death. Hemorrhagic fever viruses efficiently infect vascular endothelial cells, but are generally considered noncytopathic. Thus, the mechanism of virus-induced vascular injury remains unclear. Using the lymphocytic choriomeningitis virus variant clone 13, a prototype of Lassa virus, we show here that lethal vascular leakage in susceptible mice was completely prevented by type I IFN receptor blockade. Therefore, approaches that target type I IFNs or effector molecules induced by these cytokines may be considered for the treatment of Lassa fever and other severe hemorrhagic viral illnesses.

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Section: Ifn-i Signaling On Nonhematopoietic Cells Is Critical For Pasupporting

confidence: 56%

mentioning

confidence: 99%

Type I interferon is a therapeutic target for virus-induced lethal vascular damage

Baccalà¹,

Welch²,

Gonzalez-Quintial³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…LARGE-dependent modification of phosphorylated O-glycosylation on α-dystroglycan is essential for its ability to bind to laminin and arenaviruses at the cell surface (18). Posttranslational modification of α-dystroglycan and its interactions with various ligands have been studied to understand better the pathomechanisms of neuromuscular disease and severe LFV infections (4,5,11,12,16,18,20). However, a number of points regarding the molecular events involved in the expression of fully functional α-dystroglycan remain unclarified.…”

Section: Discussionmentioning

confidence: 99%

“…The binding sites of the arenaviruses LFV and LCMV map to the first half of the mucin-like domain of α-dystroglycan and overlap with the ECM ligand-binding domain on α-dystroglycan (11,12). As is the case for ECM protein binding, the ability of dystroglycan to function as a cellular receptor for arenaviruses depends on its posttranslational glycosylation (12). In addition, dystroglycan has been identified as a component of a cellular receptor complex for Mycobacterium leprae, the causative agent of leprosy, on Schwann cells (13).…”

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confidence: 99%

“…Hostinteraction and pathogenesis studies for LCMV have led to the development of novel concepts in immunology and virology that extend to human infections by agents including HIV, hepatitis C virus, influenza virus, other animal viruses, bacteria, and parasites (10). The binding sites of the arenaviruses LFV and LCMV map to the first half of the mucin-like domain of α-dystroglycan and overlap with the ECM ligand-binding domain on α-dystroglycan (11,12). As is the case for ECM protein binding, the ability of dystroglycan to function as a cellular receptor for arenaviruses depends on its posttranslational glycosylation (12).…”

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confidence: 99%

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Like-acetylglucosaminyltransferase (LARGE)-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection

Hara

Kanagawa

Kunz

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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109

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α-dystroglycan is a highly O-glycosylated extracellular matrix receptor that is required for anchoring of the basement membrane to the cell surface and for the entry of Old World arenaviruses into cells. Like-acetylglucosaminyltransferase (LARGE) is a key molecule that binds to the N-terminal domain of α-dystroglycan and attaches ligand-binding moieties to phosphorylated O-mannose on α-dystroglycan. Here we show that the LARGE modification required for laminin-and virus-binding occurs on specific Thr residues located at the extreme N terminus of the mucin-like domain of α-dystroglycan. Deletion and mutation analyses demonstrate that the ligand-binding activity of α-dystroglycan is conferred primarily by LARGE modification at Thr-317 and -319, within the highly conserved first 18 amino acids of the mucin-like domain. The importance of these paired residues in laminin-binding and clustering activity on myoblasts and in arenavirus cell entry is confirmed by mutational analysis with full-length dystroglycan. We further demonstrate that a sequence of five amino acids, Thr 317 ProThr 319 ProVal, contains phosphorylated O-glycosylation and, when modified by LARGE is sufficient for laminin-binding. Because the N-terminal region adjacent to the paired Thr residues is removed during posttranslational maturation of dystroglycan, our results demonstrate that the ligand-binding activity resides at the extreme N terminus of mature α-dystroglycan and is crucial for α-dystroglycan to coordinate the assembly of extracellular matrix proteins and to bind arenaviruses on the cell surface.

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ProteinO‐Mannosylation in Metazoan Organisms

Panin

Wells

2014

CP Protein Science

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Protein O-mannosylation is a special type of glycosylation that plays prominent roles in metazoans, affecting development and physiology of the nervous system and muscles. A major biological effect of O-mannosylation concentrates on the regulation of α-Dystroglycan, a membrane glycoprotein mediating cell – extracellular matrix interactions. Genetic defects of O-mannosylation result in the loss of ligand binding activity of α-Dystroglycan and causes congenital muscular dystrophies termed dystroglycanopathies. Recent progress in mass spectrometry and in vitro analyses has shed new light the mechanism of α-Dystroglycan glycosylation. However, this mechanism is underlain by complex genetic and molecular regulation that remain poorly understood. Protein O-mannosylation is evolutionarily conserved in metazoans, yet this pathway is simplified and more amenable to genetic analyses in invertebrate organisms, indicating that genetically tractable in vivo models could facilitate research in this area. This review will describe recent methodological strategies for studying protein O-mannosylation using in vitro and in vivo approaches.

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Posttranslational Modification of α-Dystroglycan, the Cellular Receptor for Arenaviruses, by the Glycosyltransferase LARGE Is Critical for Virus Binding

Cited by 139 publications

References 63 publications

Type I interferon is a therapeutic target for virus-induced lethal vascular damage

Type I interferon is a therapeutic target for virus-induced lethal vascular damage

Like-acetylglucosaminyltransferase (LARGE)-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection

ProteinO‐Mannosylation in Metazoan Organisms

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