Lassa virus entry requires a trigger-induced receptor switch

Jae, Lucas T.; Raaben, Matthijs; Herbert, Andrew S.; Kuehne, Ana I.; Wirchnianski, Ariel S.; Soh, Timothy K.; Stubbs, Sarah H.; Janssen, Hans; Damme, Markus; Säftig, Paul; Whelan, Sean P. J.; Dye, John M.; Brummelkamp, Thijn R.

doi:10.1126/science.1252480

Cited by 266 publications

(393 citation statements)

References 43 publications

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“…This places dystroglycan amongst other important pathogen receptors, including the transferrin receptor, noted for efficient internalization of extracellular ligands (Choe et al, 2011). Interestingly, LCMV and LASV have also been shown to traffic to the late endosomes, multivesicular bodies and lysosomes, mirroring our results for laminin and dystroglycan trafficking (Jae et al, 2014;Pasqual et al, 2011). Our observations of laminin trafficking to the late endosome and lysosome are supported by previous electron microscopic imaging of gold-labeled laminin-111, which revealed laminin accumulation in non-coated pits at the cell surface and in multivesicular bodies (Coopman et al, 1991).…”

Section: Discussionsupporting

confidence: 72%

Endocytic trafficking of laminin is controlled by dystroglycan and disrupted in cancers

Leonoudakis

Huang

Akhavan

et al. 2014

Journal of Cell Science

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The dynamic interactions between cells and basement membranes serve as essential regulators of tissue architecture and function in metazoans, and perturbation of these interactions contributes to the progression of a wide range of human diseases, including cancers. Here, we reveal the pathway and mechanism for the endocytic trafficking of a prominent basement membrane protein, laminin-111 (referred to here as laminin), and their disruption in disease. Livecell imaging of epithelial cells revealed pronounced internalization of laminin into endocytic vesicles. Laminin internalization was receptor mediated and dynamin dependent, and laminin proceeded to the lysosome through the late endosome. Manipulation of laminin receptor expression revealed that the dominant regulator of laminin internalization is dystroglycan, a laminin receptor that is functionally perturbed in muscular dystrophies and in many cancers. Correspondingly, laminin internalization was found to be deficient in aggressive cancer cells displaying non-functional dystroglycan, and restoration of dystroglycan function strongly enhanced the endocytosis of laminin in both breast cancer and glioblastoma cells. These results establish previously unrecognized mechanisms for the modulation of cell-basement-membrane communication in normal cells and identify a profound disruption of endocytic laminin trafficking in aggressive cancer subtypes.

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Section: Discussionsupporting

confidence: 72%

Endocytic trafficking of laminin is controlled by dystroglycan and disrupted in cancers

Leonoudakis

Huang

Akhavan

et al. 2014

Journal of Cell Science

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“…Genome-wide genetic screening in human haploid cells is a powerful tool to reveal host factors involved in entry of various pathogens, including viruses (15,16). In this study, we performed a haploid screen and demonstrate that genes involved in synthesis of sialylated glycans are essential for EV-D68 infection.…”

mentioning

confidence: 99%

Enterovirus D68 receptor requirements unveiled by haploid genetics

Baggen

Thibaut

Staring

et al. 2016

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

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Enterovirus D68 (EV-D68) is an emerging pathogen that can cause severe respiratory disease and is associated with cases of paralysis, especially among children. Heretofore, information on host factor requirements for EV-D68 infection is scarce. Haploid genetic screening is a powerful tool to reveal factors involved in the entry of pathogens. We performed a genome-wide haploid screen with the EV-D68 prototype Fermon strain to obtain a comprehensive overview of cellular factors supporting EV-D68 infection. We identified and confirmed several genes involved in sialic acid (Sia) biosynthesis, transport, and conjugation to be essential for infection. Moreover, by using knockout cell lines and gene reconstitution, we showed that both α2,6- and α2,3-linked Sia can be used as functional cellular EV-D68 receptors. Importantly, the screen did not reveal a specific protein receptor, suggesting that EV-D68 can use multiple redundant sialylated receptors. Upon testing recent clinical strains, we identified strains that showed a similar Sia dependency, whereas others could infect cells lacking surface Sia, indicating they can use an alternative, nonsialylated receptor. Nevertheless, these Sia-independent strains were still able to bind Sia on human erythrocytes, raising the possibility that these viruses can use multiple receptors. Sequence comparison of Sia-dependent and Sia-independent EV-D68 strains showed that many changes occurred near the canyon that might allow alternative receptor binding. Collectively, our findings provide insights into the identity of the EV-D68 receptor and suggest the possible existence of Sia-independent viruses, which are essential for understanding tropism and disease.

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“…In a recently described structure of the GPC protein from lymphocytic choriomeningitis virus (LCMV) in a prefusion conformation (26), the histidines that are homologous to His92 and His93 are in a slightly different orientation compared to that seen for isolated Lassa virus GP1 and have close contacts with other residues. Although LCMV enters cells independently of LAMP1 (11,26), the GP1 subunit of LASV may adopt a prefusion conformation similar to that observed in the LCMV structure. If this is true, it may explain the lower tolerance for mutation of His92 and His93.…”

Section: Discussionmentioning

confidence: 99%

“…Three fully processed glycoprotein moieties comprise the functional trimeric spike complex. It was recently shown that successful infection by LASV requires it to switch in a pH-dependent manner from the primary ␣-DG receptor to lysosome-associated membrane protein 1 (LAMP1) (11). LAMP1 (also called CD107a) is a major constituent of the lysosome membrane (12) and is thought to play an important role in maintaining lysosome integrity (13).…”

mentioning

confidence: 99%

Role of LAMP1 Binding and pH Sensing by the Spike Complex of Lassa Virus

Cohen-Dvashi

Israeli

Shani

et al. 2016

J Virol

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To effectively infect cells, Lassa virus needs to switch in an endosomal compartment from its primary receptor, ␣-dystroglycan, to a protein termed LAMP1. A unique histidine triad on the surface of the receptor-binding domain from the glycoprotein spike complex of Lassa virus is important for LAMP1 binding. Here we investigate mutated spikes that have an impaired ability to interact with LAMP1 and show that although LAMP1 is important for efficient infectivity, it is not required for spike-mediated membrane fusion per se. Our studies reveal important regulatory roles for histidines from the triad in sensing acidic pH and preventing premature spike triggering. We further show that LAMP1 requires a positively charged His230 residue to engage with the spike complex and that LAMP1 binding promotes membrane fusion. These results elucidate the molecular role of LAMP1 binding during Lassa virus cell entry and provide new insights into how pH is sensed by the spike. IMPORTANCELassa virus is a devastating disease-causing agent in West Africa, with a significant yearly death toll and severe long-term complications associated with its infection in survivors. In recent years, we learned that Lassa virus needs to switch receptors in a pHdependent manner to efficiently infect cells, but neither the molecular mechanisms that allow switching nor the actual effects of switching were known. Here we investigate the activity of the viral spike complex after abrogation of its ability to switch receptors. These studies inform us about the role of switching receptors and provide new insights into how the spike senses acidic pH.

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Lassa virus entry requires a trigger-induced receptor switch

Cited by 266 publications

References 43 publications

Endocytic trafficking of laminin is controlled by dystroglycan and disrupted in cancers

Endocytic trafficking of laminin is controlled by dystroglycan and disrupted in cancers

Enterovirus D68 receptor requirements unveiled by haploid genetics

Role of LAMP1 Binding and pH Sensing by the Spike Complex of Lassa Virus

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