Autophagy-linked plasma and lysosomal membrane protein PLAC8 is a key host factor for SARS-CoV-2 entry into human cells

Autophagy-linked plasma and lysosomal membrane protein PLAC8 is a key host factor for SARS-CoV-2 entry into human cells

Better understanding on interactions between SARS-CoV-2andhost cells should help to identify host factors that may be tar-getable to combat infection and COVID-19pathology. To this end,we have conducted a genome-wide CRISPR/Cas9-based loss-of-function screen in human lung cancer cells infected with SARS-CoV-2-pseudotyped lentiviruses. Our results recapitulate manyfindings from previous screens that used full SARS-CoV-2viruses,but also unveil two novel critical host factors: the lysosomal effluxtransporter SPNS1and the plasma and lysosomal membrane pro-tein PLAC8. Functional experiments with full SARS-CoV-2virusesconfirm that loss-of-function of these genes impairs viral entry.We find that PLAC8is a key limiting host factor, whose overexpres-sion boosts viral infection in eight different human lung cancer celllines. Using single-cell RNA-Seq data analyses, we demonstratethat PLAC8is highly expressed in ciliated and secretory cells of therespiratory tract, as well as in gut enterocytes, cell types that arehighly susceptible to SARS-CoV-2infection. Proteomics and cellbiology studies suggest that PLAC8and SPNS1regulate theautophagolysosomal compartment and affect the intracellular fateof endocytosed virions.

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Bibliographic Details
Main Authors: Ugalde, Alejandro P., Bretones, Gabriel, Rodríguez, David, Quesada, Víctor, Llorente, Francisco, Fernandez-Delgado, Raúl, Jiménez-Clavero, Miguel Ángel, Vázquez, Jesús, Calvo, Enrique, Tamargo-Gómez, Isaac, Mariño, Guillermo, Roiz-Valle, David, Maeso, Daniel, Araujo-Voces, Miguel, Español, Yaiza, Barceló, Carles, Freije, José M. P., López-Soto, Alejandro, López-Otín, Carlos
Other Authors: Instituto de Salud Carlos III
Format: artículo biblioteca
Language:English
Published: EMBO Press 2022-10-04
Subjects:Autophagy, COVID-19, Genetic screen, Plac8, Spns1,
Online Access:http://hdl.handle.net/10261/280722
http://dx.doi.org/10.13039/100011941
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/501100011033
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Summary:Better understanding on interactions between SARS-CoV-2andhost cells should help to identify host factors that may be tar-getable to combat infection and COVID-19pathology. To this end,we have conducted a genome-wide CRISPR/Cas9-based loss-of-function screen in human lung cancer cells infected with SARS-CoV-2-pseudotyped lentiviruses. Our results recapitulate manyfindings from previous screens that used full SARS-CoV-2viruses,but also unveil two novel critical host factors: the lysosomal effluxtransporter SPNS1and the plasma and lysosomal membrane pro-tein PLAC8. Functional experiments with full SARS-CoV-2virusesconfirm that loss-of-function of these genes impairs viral entry.We find that PLAC8is a key limiting host factor, whose overexpres-sion boosts viral infection in eight different human lung cancer celllines. Using single-cell RNA-Seq data analyses, we demonstratethat PLAC8is highly expressed in ciliated and secretory cells of therespiratory tract, as well as in gut enterocytes, cell types that arehighly susceptible to SARS-CoV-2infection. Proteomics and cellbiology studies suggest that PLAC8and SPNS1regulate theautophagolysosomal compartment and affect the intracellular fateof endocytosed virions.

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