Autophagy-associated dengue vesicles promote viral transmission avoiding antibody neutralization

Wu, Yang‐Chang; Mettling, Clément; Wu, Shang; Yu, Chia-Yi; Perng, Guey Chuen; Lin, Yee Shin; Lin, Yi-Ching

doi:10.1038/srep32243

Cited by 55 publications

(85 citation statements)

References 50 publications

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“…Our results corroborate previous findings and further indicate that AUP1 is necessary to facilitate virus-triggered lipophagy in support of the proposed modus operandi Randall, 2010, 2011b). This pathway might also function to supply phospholipids necessary for either altering the composition of organelles to facilitate assembly of nascent virions or for unconventional secretion of autophagyassociated dengue vesicles, as hypothesized previously (Wu et al, 2016).…”

Section: Discussionmentioning

confidence: 88%

Flaviviruses Exploit the Lipid Droplet Protein AUP1 to Trigger Lipophagy and Drive Virus Production

Zhang

Lan

et al. 2018

Cell Host & Microbe

150

188

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Ubiquitylation is one of the most versatile protein post-translational modifications and is frequently altered during virus infections. Here we employed a functional proteomics screen to identify host proteins that are differentially ubiquitylated upon dengue virus (DENV) infection. Among the several differentially modified proteins identified in infected cells was AUP1, a lipid droplet-localized type-III membrane protein, which exists predominantly in the mono-ubiquitylated form. AUP1 associated with DENV NS4A and relocalized from lipid droplets to autophagosomes upon infection. Virus production was abolished in cells deleted for AUP1 or expressing an AUP1 acyltransferase domain mutant. Ubiquitylation disrupted the AUP1-NS4A interaction, resulting in inhibited acyltransferase activity, defective lipophagy, and attenuated virus production. Our results show that DENV-NS4A exploits the acyltransferase activity of AUP1 to trigger lipophagy, a process regulated by ubiquitylation. This mechanism appears to be a general phenomenon in biogenesis of flaviviruses and underscores the critical role of post-translational modifications in virus infections.

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Section: Discussionmentioning

confidence: 88%

Flaviviruses Exploit the Lipid Droplet Protein AUP1 to Trigger Lipophagy and Drive Virus Production

Zhang

Lan

et al. 2018

Cell Host & Microbe

150

188

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“…ZIKV-induced autophagic activity in human trophoblasts restricted by pharmacological inhibition, or by deficiency in an essential autophagy gene, Atg16L1, limited ZIKV vertical transmission and improved placental and fetal outcomes, which supported a role for autophagic secretion in the process [71]. Along the same lines, it was hypothesised that DENV might evade neutralising antibodies and increase viral spread by exploiting autophagic vesicles for delivery to the extracellular medium [72]. Double staining of DENV E antigen and LC3 in a close-contact co-culture experimental set-up verified secretion of DENV-containing autophagic vesicles from donor cells, which were subsequently taken up by recipient cells.…”

Section: Non-lytic Viral Transmission By Secretory Autophagymentioning

confidence: 98%

Manipulation of autophagy by (+) RNA viruses

Wong

Sanyal

2020

Seminars in Cell & Developmental Biology

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A B S T R A C TAutophagy is an evolutionarily conserved process central to host metabolism. Among its major functions are conservation of energy during starvation, recycling organelles, and turnover of long-lived proteins. Besides, autophagy plays a critical role in removing intracellular pathogens and very likely represents a primordial intrinsic cellular defence mechanism. More recent findings indicate that it has not only retained its ability to degrade intracellular pathogens, but also functions to augment and fine tune antiviral immune responses. Interestingly, viruses have also co-evolved strategies to manipulate this pathway and use it to their advantage. Particularly intriguing is infection-dependent activation of autophagy with positive stranded (+)RNA virus infections, which benefit from the pathway without succumbing to lysosomal degradation. In this review we summarise recent data on viral manipulation of autophagy, with a particular emphasis on +RNA viruses and highlight key unanswered questions in the field that we believe merit further attention. (S. Sanyal).Seminars in Cell and Developmental Biology xxx (xxxx) xxx-xxx 1084-9521/

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“…The role that may have the presence of a DENV protein in these EVs is still not clear, although it has been reported that tetraspanin 189 bearing vesicles transport DENV in cytoplasmic prolongations of C6/36 cells [50] and other LC3-II positive large vesicles (2 to 5 μm) transport not only virus but RNA, and E, prM and NS1 proteins favoring the cell to cell transfer [51]. These results suggest that depending on the cell model, DENV infection can modulate cell death or defense processes such as apoptosis or autophagy mechanisms, kidnapping the cell transport of different types of vesicles, aimed to guarantee the movement and assembly of viral proteins and RNA and it's intracellular or extracellular spreading.…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicles of U937 macrophage cell line infected with DENV-2 induce activation in endothelial cells EA.hy926

et al. 2020

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Endothelial activation and alteration during dengue virus (DENV) infection are multifactorial events; however, the role of extracellular vesicles (EVs) in these phenomena is not known. In the present study, we characterized the EVs released by DENV-2 infected U937 macrophage cell line and evaluated the changes in the physiology and integrity of the EA.hy926 endothelial cells exposed to them. U937 macrophages were infected, supernatants were collected, and EVs were purified and characterized. Then, polarized endothelial EA.hy926 cells were exposed to the EVs for 24 h, and the transendothelial electrical resistance (TEER), monolayer permeability, and the expression of tight junction and adhesion proteins and cytokines were evaluated. The isolated EVs from infected macrophages corresponded to exosomes and apoptotic bodies, which contained the viral NS3 protein and different miRs, among other products. Exposure of EA.hy926 cells to EVs induced an increase in TEER, as well as changes in the expression of VE-cadherin and ICAM in addition leads to an increase in TNF-α, IP-10, IL-10, RANTES, and MCP-1 secretion. These results suggest that the EVs of infected macrophages transport proteins and miR that induce early changes in the physiology of the endothelium, leading to its activation and eliciting a defense program against damage during first stages of the disease, even in the absence of the virus. OPEN ACCESS Citation: Velandia-Romero ML, Calderón-Peláez MA, Balbás-Tepedino A, Márquez-Ortiz RA, Madroñero LJ, Barreto Prieto A, et al. (2020) Extracellular vesicles of U937 macrophage cell line infected with DENV-2 induce activation in endothelial cells EA.hy926. PLoS ONE 15(1): e0227030. https://doi.org/10.

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Autophagy-associated dengue vesicles promote viral transmission avoiding antibody neutralization

Cited by 55 publications

References 50 publications

Flaviviruses Exploit the Lipid Droplet Protein AUP1 to Trigger Lipophagy and Drive Virus Production

Flaviviruses Exploit the Lipid Droplet Protein AUP1 to Trigger Lipophagy and Drive Virus Production

Manipulation of autophagy by (+) RNA viruses

Extracellular vesicles of U937 macrophage cell line infected with DENV-2 induce activation in endothelial cells EA.hy926

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