Shaping the flavivirus replication complex: It is curvaceous!

Aktepe, Turgut E.; Mackenzie, Jason M.

doi:10.1111/cmi.12884

Cited by 44 publications

(43 citation statements)

References 97 publications

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“…Structural ZIKV proteins carry out the entry and membrane fusion steps of the viral life cycle 21 , while NS proteins cooperatively remodel ER membranes to form replication sites and synthesize viral RNA 22 . Despite their limited size and number, the functions of most of the NS proteins are poorly characterized 23 , as are their interactions with host lipids 24 and potentially hundreds of unique proteins 3 , 12 , 25 . While the enigmatic nature of the ZIKV NS proteins and their interactions presented challenges to defining a mechanistic basis for our lipidomics results, two lines of evidence led us to investigate NS4B as potentially important in altering lipid metabolism.…”

Section: Resultsmentioning

confidence: 99%

A global lipid map defines a network essential for Zika virus replication

et al. 2020

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Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form replication sites. How ZIKV dysregulates lipid networks to allow this, and consequences for disease, is poorly understood. Here, we perform comprehensive lipidomics to create a lipid network map during ZIKV infection. We find that ZIKV significantly alters host lipid composition, with the most striking changes seen within subclasses of sphingolipids. Ectopic expression of ZIKV NS4B protein results in similar changes, demonstrating a role for NS4B in modulating sphingolipid pathways. Disruption of sphingolipid biosynthesis in various cell types, including human neural progenitor cells, blocks ZIKV infection. Additionally, the sphingolipid ceramide redistributes to ZIKV replication sites, and increasing ceramide levels by multiple pathways sensitizes cells to ZIKV infection. Thus, we identify a sphingolipid metabolic network with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV infection.

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Section: Resultsmentioning

confidence: 99%

A global lipid map defines a network essential for Zika virus replication

et al. 2020

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“…This hypothesis is based on recent evidence supporting a role for TMEM41B in mobilizing lipids and inducing membrane curvature ( Moretti et al, 2018 ; Morita et al, 2019 ), and our own data which indicates that TMEM41B is likely recruited to flavivirus replication complexes. Flavivirus replication complexes are sites at which viral RNA replication machinery assembles within invaginations into the ER lumen utilizing host curvature-stabilizing proteins ( Aktepe and Mackenzie, 2018 ; Neufeldt et al, 2018 ; Rajah et al, 2020 ). Within these structures, dsRNA intermediates that form during viral RNA replication are protected from host innate immune sensors that survey the cytosol for pathogen associated molecular patterns (PAMPs).…”

Section: Resultsmentioning

confidence: 99%

TMEM41B is a pan-flavivirus host factor

Hoffmann

Schneider

Rozen-Gagnon

et al. 2020

Preprint

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SUMMARYFlaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection. Based on our mechanistic studies we hypothesize that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication.HIGHLIGHTSTMEM41B and VMP1 are required for both autophagy and flavivirus infection, however, autophagy is not required for flavivirus infection.TMEM41B associates with viral proteins and likely facilitates membrane remodeling to establish viral RNA replication complexes.TMEM41B single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection.TMEM41B-deficient cells display an exaggerated innate immune response upon high multiplicity flavivirus infection.

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“…Structural ZIKV proteins carry out the entry and membrane fusion steps of the viral life cycle 21 , while NS proteins cooperatively remodel ER membranes to form replication sites and synthesize viral RNA 22 . Despite their limited size and number, the functions of most of the NS proteins are poorly characterized 23 , as are their interactions with host lipids 24 and potentially hundreds of unique proteins 3,12,25 . While the enigmatic nature of the ZIKV NS proteins and their interactions presented challenges to defining a mechanistic basis for our lipidomics results, two lines of evidence led us to investigate NS4B as potentially important in altering lipid metabolism.…”

Section: Resultsmentioning

confidence: 99%

A global lipid map defines a network essential for Zika virus replication

Leier

Weinstein

Kyle

et al. 2020

Preprint

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26Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form 27 replication sites. How ZIKV dysregulates lipid networks to allow this, and consequences for 28 disease, is poorly understood. Here, we performed comprehensive lipidomics to create a lipid 29 network map during ZIKV infection. We found that ZIKV significantly alters host lipid 30 composition, with the most striking changes seen within subclasses of sphingolipids. Ectopic 31 expression of ZIKV NS4B protein resulted in similar changes, demonstrating a role for NS4B in 32 modulating sphingolipid pathways. Disruption of sphingolipid biosynthesis in various cell types, 33including human neural progenitor cells, blocked ZIKV infection. Additionally, the sphingolipid 34 ceramide redistributes to ZIKV replication sites and increasing ceramide levels by multiple 35 pathways sensitizes cells to ZIKV infection. Thus, we identify a sphingolipid metabolic network 36 with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV 37 infection. Results 112 ZIKV alters the lipid landscape of host cells 113To understand how cellular lipid metabolism is altered by ZIKV infection, we carried out 114 a global lipidomic survey of the model Huh7 human hepatic carcinoma cell line 20 infected for 24 115 or 48 hours with Asian lineage ZIKV strain FSS13025 (Fig. 1a). Lipids extracted from 116 populations of mock and infected cells (n = 5 biological replicates per condition) were analyzed 117 with electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) (Supplementary Data 118 1 and Supplementary Fig. 1a-f). We identified 340 lipid species spanning the phospholipid, 119 sphingolipid, glycerolipid, and sterol classes for which pairwise comparisons of normalized 120 abundance between mock and infected cells could be made (Supplementary Data 1). Of these, 121 80 species (23.5%) showed significant changes in abundance by 24 hours post-infection (hpi) 122 and 172 species (50.6%) were significantly altered by 48 hpi (P < 0.05, ANOVA or g-test) 123( Supplementary Data 1). Principal component analysis (PCA) of these observations confirmed 124 that infection status (mock or ZIKV) and timepoint (24 or 48 hpi) accounted most of these 125 changes, with changes in lipid composition between mock and infected cells increasing over 126 time (Fig. 1b). 127Next, we examined how ZIKV-induced changes in host lipid composition broke down by 128 subclass and species (Fig. 1c, d). A map of the pairwise correlations of all 340 species at 48 hpi 129 ( Supplementary Fig. 2a) revealed that lipid subclasses largely fell into two groups of species 130 that were either enriched or depleted in abundance ( Supplementary Fig. 2b), suggesting that 131 individual metabolic pathways are up-or down-regulated to create a specific lipid milieu around 132 the events of the viral replication cycle. Supporting this, many of the trends we observed were 133 consistent with earlier reports of functional roles for lipids during flavivirus infection. In ...

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Shaping the flavivirus replication complex: It is curvaceous!

Cited by 44 publications

References 97 publications

A global lipid map defines a network essential for Zika virus replication

A global lipid map defines a network essential for Zika virus replication

TMEM41B is a pan-flavivirus host factor

A global lipid map defines a network essential for Zika virus replication

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