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© A-M. Pais-Correia, M-I. Thoulouze, A. Alcover, A. Gessain
Mise en évidence de structures de type "biofilm ", formées par le rétrovirus HTLV-1 générés par des cellules infectées (cellules du haut), qui ont été transmis à un autre lymphocyte (cellule du bas). Micrographie en microscopie électronique à balayage. Image colorisée.
Publication : Journal of virology

A genome-wide CRISPR-Cas9 screen identifies the dolichol-phosphate mannose synthase complex as a host dependency factor for dengue virus infection

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Journal of virology - 08 Jan 2020

Labeau A, Simon-Loriere E, Hafirassou ML, Bonnet-Madin L, Tessier S, Zamborlini A, Dupré T, Seta N, Schwartz O, Chaix ML, Delaugerre C, Amara A, Meertens L

Link to Pubmed [PMID] – 31915280

J. Virol. 2020 Jan;

Dengue virus (DENV) is a mosquito-borne flavivirus responsible for dengue disease, a major human health concern for which no specific therapies are available. Like other viruses, DENV relies heavily on the host cellular machinery for productive infection. Here, we performed a genome-wide CRISPR-Cas9 screen using haploid HAP1 cells to identify host genes important for DENV infection. We identified DPM1 and 3, two subunits of the ER resident DPM synthase (DPMS) complex, as host dependency factors for DENV and other related flaviviruses such as Zika virus (ZIKV). DPMS complex catalyzes the synthesis of dolichol-phosphate mannose (DPM) which serves as mannosyl donor in pathways leading to N-glycosylation, GPI anchor biosynthesis and C- or O-mannosylation of proteins in the ER lumen. Mutation in the DXD motif of DPM1, which is essential for its catalytic activity, abolished DPMS-mediated DENV infection. Similarly, genetic ablation of ALG3, a mannosyltransferase that transfers mannose to lipid-linked oligosaccharide (LLO), rendered cells poorly susceptible to DENV. We also established that in cells deficient for DPMS activity, viral RNA amplification is hampered and truncated oligosaccharides are transferred to the viral prM and E glycoproteins, affecting their proper folding. Overall, our study provides new insights into the host dependent mechanisms of DENV infection and supports current therapeutic approaches using glycosylation inhibitors to treat DENV infection. Dengue disease, which is caused by dengue virus (DENV), has emerged as the most important mosquito-borne viral disease in humans and is a major global health concern. DENV encodes only few proteins and relies on the host cell machinery to accomplish its life cycle. The identification of the host factors important for DENV infection is needed to propose new targets for antiviral intervention. Using a genome-wide CRISPR-Cas9 screen, we identified DPM1 and 3, two subunits of the DPMS complex, as important host factors for the replication of DENV as well as others related viruses such as Zika virus. We established that DPMS complex plays a dual role during viral infection, both regulating viral RNA replication and promoting viral structural glycoproteins folding/stability. These results provide insights into the host molecules exploited by DENV and other flaviviruses to facilitate their life cycle.

https://www.ncbi.nlm.nih.gov/pubmed/31915280