Viperin interacts with PEX19 to mediate peroxisomal augmentation of the innate antiviral response

Khantisitthiporn, Onruedee; Shue, Byron; Eyre, Nicholas S.; Nash, Colt W; Turnbull, Lynne; Whitchurch, Cynthia B.; Hoek, Kylie H. Van der; Helbig, Karla J.; Beard, Michael R.

doi:10.26508/lsa.202000915

Cited by 7 publications

(5 citation statements)

References 46 publications

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“…Proximity ligation assay was performed as described previously ( 55 ). Briefly, proximity ligation kits (Duolink PLA) were purchased from Sigma-Aldrich and the manufacturer’s protocol was followed.…”

Section: Methodsmentioning

confidence: 99%

Genome-Wide CRISPR Screen Identifies RACK1 as a Critical Host Factor for Flavivirus Replication

Shue

Chiramel

Cerikan

et al. 2021

J Virol

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Cellular factors have important roles in all facets of the flavivirus replication cycle. Deciphering viral-host protein interactions is essential for understanding the flavivirus lifecycle as well as development of effective antiviral strategies. To uncover novel host factors that are co-opted by multiple flaviviruses, a CRISPR/Cas9 genome wide knockout (KO) screen was employed to identify genes required for replication of Zika virus (ZIKV). Receptor for Activated Protein C Kinase 1 (RACK1) was identified as a novel host factor required for ZIKV replication, which was confirmed via complementary experiments. Depletion of RACK1 via siRNA demonstrated that RACK1 is important for replication of a wide range of mosquito- and tick-borne flaviviruses, including West Nile Virus (WNV), Dengue Virus (DENV), Powassan Virus (POWV) and Langat Virus (LGTV) as well as the coronavirus SARS-CoV-2, but not for YFV, EBOV, VSV or HSV. Notably, flavivirus replication was only abrogated when RACK1 expression was dampened prior to infection. Utilising a non-replicative flavivirus model, we show altered morphology of viral replication factories and reduced formation of vesicle packets (VPs) in cells lacking RACK1 expression. In addition, RACK1 interacted with NS1 protein from multiple flaviviruses; a key protein for replication complex formation. Overall, these findings reveal RACK1’s crucial role to the biogenesis of pan-flavivirus replication organelles. Importance Cellular factors are critical in all facets of viral lifecycles, where overlapping interactions between the virus and host can be exploited as possible avenues for the development of antiviral therapeutics. Using a genome-wide CRISPR knock-out screening approach to identify novel cellular factors important for flavivirus replication we identified RACK1 as a pro-viral host factor for both mosquito- and tick-borne flaviviruses in addition to SARS-CoV-2. Using an innovative flavivirus protein expression system, we demonstrate for the first time the impact of the loss of RACK1 on the formation of viral replication factories known as 'vesicle packets' (VPs). In addition, we show that RACK1 can interact with numerous flavivirus NS1 proteins as a potential mechanism by which VP formation can be induced by the former.

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Section: Methodsmentioning

confidence: 99%

Genome-Wide CRISPR Screen Identifies RACK1 as a Critical Host Factor for Flavivirus Replication

Shue

Chiramel

Cerikan

et al. 2021

J Virol

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“…Of note, following infection, MAVS is also found at regions of interaction between mitochondria and peroxisomes [421]. One report suggests that the viperin protein, through interactions with PEX19, repositions these two regions of MAVS localization more proximally to potentiate signaling [422]. MAVS interaction with the RLR triggers MAVS oligomerization and formation of a signalosome, with activation by one of two other MAM proteins, TNF receptor‐associated factor (TRAF) or inhibitor of kappa‐B kinase (IKK).…”

Section: Provisional Mam Subsetsmentioning

confidence: 99%

Balancing life and death: BCL‐2 family members at diverse ER–mitochondrial contact sites

Means

Katz

2021

The FEBS Journal

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The outer mitochondrial membrane is a busy place. One essential activity for cellular survival is the regulation of membrane integrity by the BCL‐2 family of proteins. Another critical facet of the outer mitochondrial membrane is its close approximation with the endoplasmic reticulum. These mitochondrial‐associated membranes (MAMs) occupy a significant fraction of the mitochondrial surface and serve as key signaling hubs for multiple cellular processes. Each of these pathways may be considered as forming their own specialized MAM subtype. Interestingly, like membrane permeabilization, most of these pathways play critical roles in regulating cellular survival and death. Recently, the pro‐apoptotic BCL‐2 family member BOK has been found within MAMs where it plays important roles in their structure and function. This has led to a greater appreciation that multiple BCL‐2 family proteins, which are known to participate in numerous functions throughout the cell, also have roles within MAMs. In this review, we evaluate several MAM subsets, their role in cellular homeostasis, and the contribution of BCL‐2 family members to their functions.

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“…It has been observed that LDs that are in association with viperin can translocate to peroxisomes if this complex is not formed. It is difficult to find a peroxisome associated with LDs; this fact shows the importance of LDs in activating ISGs against viral infections [ 41 , 42 , 43 ]. While viperin can bind to other proteins to trigger an interferon response, it has been observed that it can only translocate to LDs to catalyze CTP conversion to ddhCTP, which is a ribonucleotide that serves as a terminator of viral RNA synthesis [ 44 ].…”

Section: Exploring the Multifaceted Roles Of Lipid Droplets And Their...mentioning

confidence: 99%

Multifaceted Nature of Lipid Droplets in Viral Interactions and Pathogenesis

Herrera-Moro Huitron,

De Jesús-González,

Martínez-Castillo

et al. 2023

Microorganisms

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Once regarded as inert organelles with limited and ill-defined roles, lipid droplets (LDs) have emerged as dynamic entities with multifaceted functions within the cell. Recent research has illuminated their pivotal role as primary energy reservoirs in the form of lipids, capable of being metabolized to meet cellular energy demands. Their high dynamism is underscored by their ability to interact with numerous cellular organelles, notably the endoplasmic reticulum (the site of LD genesis) and mitochondria, which utilize small LDs for energy production. Beyond their contribution to cellular bioenergetics, LDs have been associated with viral infections. Evidence suggests that viruses can co-opt LDs to facilitate their infection cycle. Furthermore, recent discoveries highlight the role of LDs in modulating the host’s immune response. Observations of altered LD levels during viral infections suggest their involvement in disease pathophysiology, potentially through production of proinflammatory mediators using LD lipids as precursors. This review explores these intriguing aspects of LDs, shedding light on their multifaceted nature and implications in viral interactions and disease development.

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Viperin interacts with PEX19 to mediate peroxisomal augmentation of the innate antiviral response

Cited by 7 publications

References 46 publications

Genome-Wide CRISPR Screen Identifies RACK1 as a Critical Host Factor for Flavivirus Replication

Genome-Wide CRISPR Screen Identifies RACK1 as a Critical Host Factor for Flavivirus Replication

Balancing life and death: BCL‐2 family members at diverse ER–mitochondrial contact sites

Multifaceted Nature of Lipid Droplets in Viral Interactions and Pathogenesis

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