통찰 - Molecular Biology - # Regulation of m6A Modification on Interferon-Stimulated Genes by WTAP Phase Transition

Phase Transition of WTAP Regulates m6A Modification of Interferon-Stimulated Genes

Q: How does the phase transition of WTAP and its regulation of m6A modification on ISGs mRNA contribute to the overall antiviral response beyond the specific context of IFN-β stimulation?

The phase transition of WTAP from aggregates to liquid droplets plays a crucial role in the regulation of m6A modification on interferon-stimulated genes (ISGs) mRNA, which is essential for the antiviral response. Beyond the specific context of IFN-β stimulation, this phase transition mechanism allows for a rapid and dynamic response to various viral infections. The ability of WTAP to transition between different states enables it to effectively recruit the m6A methyltransferase complex (MTC) and transcription factors like STAT1 to the promoter regions of ISGs, facilitating co-transcriptional m6A modification. This modification can influence the stability, translation, and degradation of mRNA, thereby fine-tuning the expression of ISGs that are critical for mounting an effective antiviral response. Moreover, the phase transition of WTAP may also allow for a more generalized mechanism of mRNA regulation in response to other cytokines or stress signals, not limited to IFN-β. For instance, during various immune responses, the ability of WTAP to modulate m6A levels on different subsets of mRNAs could help in adjusting the cellular machinery to combat diverse pathogens. This suggests that the phase transition of WTAP is a versatile regulatory mechanism that can adapt to different signaling contexts, enhancing the overall antiviral response by ensuring that the appropriate ISGs are expressed at the right time and in the right amounts.

Q: What other cellular processes or signaling pathways might be influenced by the phase transition-dependent functions of WTAP in regulating mRNA modifications?

The phase transition-dependent functions of WTAP in regulating mRNA modifications could influence several other cellular processes and signaling pathways beyond antiviral responses. For instance, the dynamic nature of WTAP's phase separation may play a role in cellular differentiation, development, and stress responses. In stem cells, m6A modification has been shown to regulate differentiation pathways, and the ability of WTAP to transition between states could be critical in determining cell fate decisions. Additionally, the phase transition of WTAP may impact the regulation of genes involved in inflammation, apoptosis, and cell cycle progression. By modulating m6A levels on mRNAs associated with these pathways, WTAP could influence the stability and translation of key regulatory proteins, thereby affecting cellular responses to various stimuli. For example, during inflammatory responses, the timely regulation of m6A modifications on pro-inflammatory cytokines could help in resolving inflammation and restoring homeostasis. Furthermore, the interaction of phase-separated WTAP with other RNA-binding proteins and transcription factors could create a network of regulatory mechanisms that coordinate gene expression in response to environmental changes, thereby influencing pathways such as metabolic regulation and cellular stress responses.

Q: Could the insights into WTAP phase transition and its role in bridging transcriptional and post-transcriptional regulation be leveraged to develop novel therapeutic strategies for viral infections or other diseases involving dysregulated mRNA modifications?

Yes, the insights into WTAP phase transition and its role in bridging transcriptional and post-transcriptional regulation present promising avenues for developing novel therapeutic strategies for viral infections and other diseases characterized by dysregulated mRNA modifications. Targeting the phase transition dynamics of WTAP could provide a means to modulate m6A modification levels on specific mRNAs, thereby influencing gene expression profiles critical for disease progression. For viral infections, enhancing the phase transition of WTAP could potentially improve the antiviral response by promoting the expression of ISGs that are crucial for combating viral replication. Conversely, in diseases where m6A modifications are dysregulated, such as certain cancers or metabolic disorders, small molecules or peptides that stabilize WTAP in its liquid droplet state could be developed to restore normal mRNA modification patterns and gene expression. Additionally, understanding the molecular mechanisms governing WTAP's phase transition could lead to the identification of biomarkers for disease states or therapeutic targets. For instance, modulating the activity of phosphatases like PPP4, which regulate WTAP's phosphorylation state and phase behavior, could be explored as a therapeutic strategy to influence mRNA modifications in various pathological contexts. Overall, leveraging the knowledge of WTAP's phase transition and its regulatory functions could pave the way for innovative treatments that target the underlying mechanisms of mRNA modification in viral infections and other diseases.

핵심 개념

IFN-β-induced dephosphorylation of WTAP promotes its phase transition from aggregates to liquid droplets, which enables WTAP to recruit the m6A methyltransferase complex and transcription factor STAT1 to the promoter regions of interferon-stimulated genes, leading to co-transcriptional m6A modification and regulation of ISG expression.

초록

The content explores the mechanism by which the m6A methyltransferase adaptor protein WTAP regulates the m6A modification of interferon-stimulated genes (ISGs) in response to IFN-β stimulation.

Key highlights:

WTAP undergoes phase transition from aggregates to liquid droplets upon IFN-β stimulation, driven by dephosphorylation mediated by the phosphatase PPP4.
The liquid-phase separated WTAP interacts with the transcription factor STAT1 and recruits the m6A methyltransferase complex (MTC) to the promoter regions of ISGs, enabling co-transcriptional m6A modification of ISG mRNAs.
The m6A modification of ISG mRNAs regulates their expression and stability, thereby fine-tuning the antiviral type I interferon response.
Disruption of WTAP phase transition, either by inhibiting dephosphorylation or mimicking constitutive phosphorylation, impairs the recruitment of MTC to ISG promoters and reduces m6A modification of ISG mRNAs.

The study reveals a novel mechanism by which WTAP phase transition bridges transcriptional regulation and post-transcriptional mRNA modification to precisely control the expression of antiviral genes.

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biorxiv.org

통계

"WTAP clustered and formed condensate-like pattern in cells during virus infection."
"IFN-β stimulation promoted the increasing number of WTAP condensates formation."
"Recombinant mCherry-WTAP underwent phase separation in vitro."
"IFN-β stimulation promoted the phase transition of WTAP from aggregates to liquid droplets in cells."
"Phosphorylation of WTAP was significantly decreased under IFN-β stimulation."
"IFN-β stimulation promoted the interaction between WTAP and the phosphatase PPP4."
"Knockdown of PPP4 enhanced the phosphorylation level of WTAP in IFN-β treated cells."
"Phosphorylation-mimic WTAP mutant (5ST-D) formed aggregates, while phosphorylation-deficient mutant (5ST-A) formed liquid droplets."

인용구

"IFN-β-induced dephosphorylation promotes the transition from aggregates to liquid-phase of WTAP both in vitro and in cells."
"Liquid-phase of WTAP increased the mobility of WTAP droplets, and recruited METTL3 and nucleus-translocated STAT1 together to form STAT1-WTAP-METTL3 droplets."
"Leading by transcriptional factor STAT1, the droplets were able to directly bind with ISGs promoter region, and conducted the m6A modification of ISGs mRNA during the STAT1-mediated transcription process, thereby prompting diverse regulation of ISGs mRNA."

핵심 통찰 요약

Phase transition of WTAP regulates m6A modification of interferon-stimulated genes

by Cai,S., Zhou... 게시일 www.biorxiv.org 07-22-2024

https://www.biorxiv.org/content/10.1101/2024.07.18.604157v1

더 깊은 질문

How does the phase transition of WTAP and its regulation of m6A modification on ISGs mRNA contribute to the overall antiviral response beyond the specific context of IFN-β stimulation?

The phase transition of WTAP from aggregates to liquid droplets plays a crucial role in the regulation of m6A modification on interferon-stimulated genes (ISGs) mRNA, which is essential for the antiviral response. Beyond the specific context of IFN-β stimulation, this phase transition mechanism allows for a rapid and dynamic response to various viral infections. The ability of WTAP to transition between different states enables it to effectively recruit the m6A methyltransferase complex (MTC) and transcription factors like STAT1 to the promoter regions of ISGs, facilitating co-transcriptional m6A modification. This modification can influence the stability, translation, and degradation of mRNA, thereby fine-tuning the expression of ISGs that are critical for mounting an effective antiviral response.
Moreover, the phase transition of WTAP may also allow for a more generalized mechanism of mRNA regulation in response to other cytokines or stress signals, not limited to IFN-β. For instance, during various immune responses, the ability of WTAP to modulate m6A levels on different subsets of mRNAs could help in adjusting the cellular machinery to combat diverse pathogens. This suggests that the phase transition of WTAP is a versatile regulatory mechanism that can adapt to different signaling contexts, enhancing the overall antiviral response by ensuring that the appropriate ISGs are expressed at the right time and in the right amounts.

What other cellular processes or signaling pathways might be influenced by the phase transition-dependent functions of WTAP in regulating mRNA modifications?

The phase transition-dependent functions of WTAP in regulating mRNA modifications could influence several other cellular processes and signaling pathways beyond antiviral responses. For instance, the dynamic nature of WTAP's phase separation may play a role in cellular differentiation, development, and stress responses. In stem cells, m6A modification has been shown to regulate differentiation pathways, and the ability of WTAP to transition between states could be critical in determining cell fate decisions.
Additionally, the phase transition of WTAP may impact the regulation of genes involved in inflammation, apoptosis, and cell cycle progression. By modulating m6A levels on mRNAs associated with these pathways, WTAP could influence the stability and translation of key regulatory proteins, thereby affecting cellular responses to various stimuli. For example, during inflammatory responses, the timely regulation of m6A modifications on pro-inflammatory cytokines could help in resolving inflammation and restoring homeostasis.
Furthermore, the interaction of phase-separated WTAP with other RNA-binding proteins and transcription factors could create a network of regulatory mechanisms that coordinate gene expression in response to environmental changes, thereby influencing pathways such as metabolic regulation and cellular stress responses.

Could the insights into WTAP phase transition and its role in bridging transcriptional and post-transcriptional regulation be leveraged to develop novel therapeutic strategies for viral infections or other diseases involving dysregulated mRNA modifications?

Yes, the insights into WTAP phase transition and its role in bridging transcriptional and post-transcriptional regulation present promising avenues for developing novel therapeutic strategies for viral infections and other diseases characterized by dysregulated mRNA modifications. Targeting the phase transition dynamics of WTAP could provide a means to modulate m6A modification levels on specific mRNAs, thereby influencing gene expression profiles critical for disease progression.
For viral infections, enhancing the phase transition of WTAP could potentially improve the antiviral response by promoting the expression of ISGs that are crucial for combating viral replication. Conversely, in diseases where m6A modifications are dysregulated, such as certain cancers or metabolic disorders, small molecules or peptides that stabilize WTAP in its liquid droplet state could be developed to restore normal mRNA modification patterns and gene expression.
Additionally, understanding the molecular mechanisms governing WTAP's phase transition could lead to the identification of biomarkers for disease states or therapeutic targets. For instance, modulating the activity of phosphatases like PPP4, which regulate WTAP's phosphorylation state and phase behavior, could be explored as a therapeutic strategy to influence mRNA modifications in various pathological contexts.
Overall, leveraging the knowledge of WTAP's phase transition and its regulatory functions could pave the way for innovative treatments that target the underlying mechanisms of mRNA modification in viral infections and other diseases.