洞察 - Molecular Biology - # Zika Virus Hijacking of Host IGF2BP2 Ribonucleoprotein Complex

Zika Virus Hijacks and Remodels the IGF2BP2 Ribonucleoprotein Complex to Promote Viral Replication Organelle Biogenesis

Q: How might the virus-induced changes in IGF2BP2 phosphorylation status contribute to the remodeling of its RNA and protein interactomes?

The phosphorylation status of IGF2BP2 is crucial for its function as an RNA-binding protein and its interactions with various cellular partners. Zika virus (ZIKV) infection has been shown to decrease the phosphorylation of specific serine residues (Ser162) on IGF2BP2, which may alter its affinity for certain mRNA ligands and protein partners. This reduction in phosphorylation could lead to a decreased interaction with mRNAs that are typically bound by IGF2BP2, such as TNRC6A and PUM2, which are known to be involved in post-transcriptional regulation. Consequently, the remodeling of IGF2BP2's RNA interactome may result in a shift in the stability and translation of these mRNAs, potentially affecting cellular processes that are critical for viral replication. Additionally, the altered phosphorylation state may influence the protein interactome of IGF2BP2, leading to changes in its association with splicing factors and other proteins involved in RNA metabolism. This dynamic interplay between phosphorylation and protein interactions underscores the complexity of host-virus interactions and highlights how ZIKV can manipulate host cellular machinery to favor its replication.

Q: What are the potential mechanisms by which the altered IGF2BP2 interactions with mRNA splicing factors impact ZIKV replication?

The altered interactions of IGF2BP2 with mRNA splicing factors during ZIKV infection can significantly impact viral replication through several mechanisms. First, the decreased association of IGF2BP2 with splicing factors may disrupt the normal splicing of host mRNAs, leading to the accumulation of unspliced or improperly processed transcripts. This could affect the expression of host proteins that are critical for antiviral responses or cellular homeostasis, thereby creating a more favorable environment for viral replication. Second, the remodeling of the IGF2BP2 ribonucleoprotein complex may also influence the splicing of viral RNA. ZIKV is known to alter mRNA splicing patterns, and if IGF2BP2 is less available to interact with splicing factors, this could lead to changes in the splicing of viral transcripts, potentially enhancing the production of viral proteins necessary for replication. Lastly, the interaction of IGF2BP2 with mRNA splicing factors may also play a role in the regulation of the cellular stress response. ZIKV infection can induce cellular stress, and the ability of IGF2BP2 to modulate splicing factor interactions may help the virus evade host immune responses. By altering the splicing of key regulatory proteins, ZIKV can manipulate the host cell's response to infection, thereby promoting its own replication.

Q: Could the insights into IGF2BP2 hijacking by ZIKV lead to the development of novel antiviral strategies targeting host-virus interactions?

Yes, the insights into how ZIKV hijacks IGF2BP2 to facilitate its replication can pave the way for the development of novel antiviral strategies that target host-virus interactions. By understanding the specific mechanisms through which ZIKV alters IGF2BP2's phosphorylation status and its interactions with RNA and protein partners, researchers can identify potential therapeutic targets. For instance, small molecules or peptides that mimic the phosphorylation state of IGF2BP2 could be designed to restore its normal interactions with mRNA splicing factors, thereby enhancing the host's antiviral response. Additionally, targeting the specific binding sites of IGF2BP2 on viral RNA or its interaction with viral proteins like NS5 could disrupt the viral replication cycle. Furthermore, the identification of other host factors that are co-opted by ZIKV in a similar manner to IGF2BP2 could lead to a broader strategy of targeting host pathways that are essential for viral replication. This approach could minimize the risk of developing resistance, as it would disrupt the virus's ability to exploit host cellular machinery. Overall, leveraging the understanding of IGF2BP2's role in ZIKV replication could lead to innovative antiviral therapies that enhance host defenses against the virus.

核心概念

Zika virus hijacks and remodels the host IGF2BP2 ribonucleoprotein complex to regulate viral replication organelle biogenesis and viral RNA synthesis.

摘要

The study investigates the role of host RNA-binding proteins (RBPs) in the replication of Zika virus (ZIKV) and Dengue virus (DENV). Through an RNAi mini-screen, the authors identified insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) as a specific host dependency factor for ZIKV replication.

Key highlights:

In ZIKV-infected cells, IGF2BP2 associates with the viral NS5 polymerase and redistributes to the perinuclear viral replication compartment.
IGF2BP2 directly interacts with the 3' and 5' untranslated regions (UTRs) of the ZIKV RNA genome.
Knockdown of IGF2BP2 impairs de novo viral replication organelle (vRO) biogenesis and viral RNA synthesis, but not viral RNA translation.
ZIKV infection alters the protein and RNA interactomes of IGF2BP2, including decreased interactions with mRNA splicing factors.
The authors propose that ZIKV hijacks and remodels the IGF2BP2 ribonucleoprotein complex to regulate vRO biogenesis and viral RNA neosynthesis.

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统计

ZIKV infection decreases the interaction between IGF2BP2 and TNRC6A and PUM2 mRNAs, while the interaction with CIRBP mRNA remains unchanged.
IGF2BP2 directly binds to the 3' and 5' UTRs of the ZIKV RNA genome with Kd values of 418 nM and 203 nM, respectively.
ZIKV infection increases the interaction between IGF2BP2 and the ER-shaping protein ATL2 by 14-fold.

引用

"IGF2BP2 positively regulates ZIKV genome replication (but not its translation), which is most likely mediated through its interactions with NS5 and vRNA."
"Using a recently engineered replication-independent VP induction system, we identified IGF2BP2 as a novel regulator of ZIKV de novo VP biogenesis."
"Our interactome analysis revealed global changes in the composition of IGF2BP2 RNP with 62 cellular proteins whose association with IGF2BP2 was altered during ZIKV infection."

从中提取的关键见解

Zika virus remodels and hijacks IGF2BP2 ribonucleoprotein complex to promote viral replication organelle biogenesis

by Mazeaud,C., ... 在 www.biorxiv.org 12-11-2023

https://www.biorxiv.org/content/10.1101/2023.12.08.570783v2

更深入的查询

How might the virus-induced changes in IGF2BP2 phosphorylation status contribute to the remodeling of its RNA and protein interactomes?

The phosphorylation status of IGF2BP2 is crucial for its function as an RNA-binding protein and its interactions with various cellular partners. Zika virus (ZIKV) infection has been shown to decrease the phosphorylation of specific serine residues (Ser162) on IGF2BP2, which may alter its affinity for certain mRNA ligands and protein partners. This reduction in phosphorylation could lead to a decreased interaction with mRNAs that are typically bound by IGF2BP2, such as TNRC6A and PUM2, which are known to be involved in post-transcriptional regulation. Consequently, the remodeling of IGF2BP2's RNA interactome may result in a shift in the stability and translation of these mRNAs, potentially affecting cellular processes that are critical for viral replication. Additionally, the altered phosphorylation state may influence the protein interactome of IGF2BP2, leading to changes in its association with splicing factors and other proteins involved in RNA metabolism. This dynamic interplay between phosphorylation and protein interactions underscores the complexity of host-virus interactions and highlights how ZIKV can manipulate host cellular machinery to favor its replication.

What are the potential mechanisms by which the altered IGF2BP2 interactions with mRNA splicing factors impact ZIKV replication?

The altered interactions of IGF2BP2 with mRNA splicing factors during ZIKV infection can significantly impact viral replication through several mechanisms. First, the decreased association of IGF2BP2 with splicing factors may disrupt the normal splicing of host mRNAs, leading to the accumulation of unspliced or improperly processed transcripts. This could affect the expression of host proteins that are critical for antiviral responses or cellular homeostasis, thereby creating a more favorable environment for viral replication.
Second, the remodeling of the IGF2BP2 ribonucleoprotein complex may also influence the splicing of viral RNA. ZIKV is known to alter mRNA splicing patterns, and if IGF2BP2 is less available to interact with splicing factors, this could lead to changes in the splicing of viral transcripts, potentially enhancing the production of viral proteins necessary for replication.
Lastly, the interaction of IGF2BP2 with mRNA splicing factors may also play a role in the regulation of the cellular stress response. ZIKV infection can induce cellular stress, and the ability of IGF2BP2 to modulate splicing factor interactions may help the virus evade host immune responses. By altering the splicing of key regulatory proteins, ZIKV can manipulate the host cell's response to infection, thereby promoting its own replication.

Could the insights into IGF2BP2 hijacking by ZIKV lead to the development of novel antiviral strategies targeting host-virus interactions?

Yes, the insights into how ZIKV hijacks IGF2BP2 to facilitate its replication can pave the way for the development of novel antiviral strategies that target host-virus interactions. By understanding the specific mechanisms through which ZIKV alters IGF2BP2's phosphorylation status and its interactions with RNA and protein partners, researchers can identify potential therapeutic targets.
For instance, small molecules or peptides that mimic the phosphorylation state of IGF2BP2 could be designed to restore its normal interactions with mRNA splicing factors, thereby enhancing the host's antiviral response. Additionally, targeting the specific binding sites of IGF2BP2 on viral RNA or its interaction with viral proteins like NS5 could disrupt the viral replication cycle.
Furthermore, the identification of other host factors that are co-opted by ZIKV in a similar manner to IGF2BP2 could lead to a broader strategy of targeting host pathways that are essential for viral replication. This approach could minimize the risk of developing resistance, as it would disrupt the virus's ability to exploit host cellular machinery. Overall, leveraging the understanding of IGF2BP2's role in ZIKV replication could lead to innovative antiviral therapies that enhance host defenses against the virus.