SARS-CoV-2 hijacks Golgi bound PI4P to trigger activation of DNA damage response kinase ATM in cytoplasm

Medical News: A collaborative study led by scientists at the Université de Montpellier in France has uncovered a remarkable tactic employed by SARS-CoV-2 to hijack human cellular machinery. The virus, known for causing COVID-19, manipulates key lipid transport systems within human cells to facilitate its replication. This finding not only deepens our understanding of how SARS-CoV-2 operates but also opens doors to new therapeutic strategies. The research was conducted by experts at the Institute of Research in Infectious Diseases (IRIM) and the Center for Research in Biochemistry and Molecular Biology (CRBM) at the Université de Montpellier, highlighting the role of lipid molecules in viral survival and reproduction.


SARS-CoV-2 hijacks Golgi bound PI4P to trigger activation of DNA damage response kinase ATM in cytoplasm

How the Virus Targets Host Cellular Pathways
SARS-CoV-2, like all viruses, cannot survive or replicate independently - it needs a host. The study shows that the virus strategically targets a lipid called phosphatidylinositol-4-phosphate (PI4P), a molecule essential for the proper functioning of the Golgi apparatus, an organelle in human cells. By using the oxysterol-binding protein 1 (OSBP1), the virus extracts PI4P from the Golgi, effectively depleting it from its natural reservoir. This depletion sets off a cascade of molecular events, leading to the activation of the Ataxia-Telangiectasia-Mutated (ATM) kinase.
 
ATM is traditionally a nuclear protein that responds to DNA damage. In an unexpected twist, the study discovered that SARS-CoV-2 activates ATM in the cytoplasm, breaking its usual nuclear constraints. This Medical News report explores how this novel interaction between SARS-CoV-2 and cellular components could influence disease severity and present potential drug targets.
 
Key Findings from the Research
The study revealed several unprecedented insights:
 
-Hijacking PI4P Pools: SARS-CoV-2 diverts PI4P from the Golgi apparatus, impairing its natural roles. PI4P is typically involved in maintaining Golgi structure, facilitating protein trafficking, and regulating lipid distribution. By draining PI4P, the virus disrupts normal cellular function while supporting its replication needs.
 
-Cytoplasmic Activation of ATM: ATM, a key protein in the DNA damage response (DDR), is usually inactive when bound to PI4P in the Golgi. Upon PI4P depletion, ATM dissociates and becomes activated in the cytoplasm. This cytoplasmic activation primes the protein for rapid responses to DNA damage, even in the absence of traditional damage signals.
 
-Critical Role of ATM in Viral Replication: Pharmacological inhibitors that block ATM activation significantly reduced SARS-CoV-2 replication. This demonstrates that the virus relies on this altered state of ATM for efficient replication, potentially exploiting it to manage cellular stress during infection.
 
> -Broader Implications for Human Coronaviruses: The researchers tested the effects of PI4P manipulation and ATM inhibition on another coronavirus, HCoV-229E, and found similar results. This suggests that the exploitation of PI4P and ATM activation might be a conserved strategy among coronaviruses.
 
-Vulnerability of Cancer Patients: Cancer patients undergoing chemotherapy or radiotherapy were already known to be at higher risk for severe COVID-19 outcomes. This study suggests a molecular explanation: SARS-CoV-2 infection primes ATM to react faster to DNA damage, potentially exacerbating the effects of cancer treatments.
 
A Closer Look at the Molecular Mechanisms
SARS-CoV-2 achieves its objectives by manipulating OSBP1, a protein that naturally transfers PI4P between cellular compartments. Normally, OSBP1 exchanges PI4P from the Golgi for cholesterol from the endoplasmic reticulum. The virus takes over this transport system to funnel PI4P to its replication sites. As PI4P is siphoned off, the Golgi's structural integrity begins to falter, impacting cellular processes like protein sorting and trafficking.
 
Furthermore, by depleting PI4P, SARS-CoV-2 indirectly activates ATM, which becomes untethered from the Golgi and undergoes auto-phosphorylation. This activation transforms ATM into a cytoplasmic kinase, a phenomenon rarely observed under normal conditions. The activation of cytoplasmic ATM not only aids the virus in overcoming cellular defenses but also primes the cell to respond more aggressively to subsequent DNA damage.
 
Implications for Therapeutic Strategies
The discovery that ATM activation is critical for SARS-CoV-2 replication highlights the therapeutic potential of targeting this pathway. ATM inhibitors, such as AZD0156, were shown to significantly impair viral replication in laboratory models. By stabilizing ATM in its inactive state, these inhibitors prevent the virus from exploiting the ATM-PI4P interaction.
 
Interestingly, the study found that while pharmacological inhibition of ATM had a profound antiviral effect, the complete removal of ATM through genetic methods did not impact viral replication. This indicates that the virus relies specifically on the altered, cytoplasmic form of ATM for its replication, underscoring the precision of its strategy.
 
The Role of PI4P Across Coronaviruses
The study also sheds light on a potential conserved mechanism across coronaviruses. By testing the effects of PI4P manipulation on HCoV-229E, a common cold virus, researchers observed similar reliance on PI4P and ATM. This suggests that therapies targeting PI4P metabolism or ATM activation could be broadly effective against multiple coronaviruses, not just SARS-CoV-2.
 
Impact on Vulnerable Populations
Cancer patients, particularly those undergoing therapies that cause DNA damage, are at heightened risk of severe COVID-19. The study provides a molecular basis for this vulnerability. The infection-induced activation of ATM in the cytoplasm may exacerbate DNA damage responses triggered by chemotherapy or radiation, leading to increased inflammation and cellular stress. This could contribute to the cytokine storms often observed in severe COVID-19 cases, further complicating recovery.
 
Concluding Remarks
This research provides a comprehensive view of how SARS-CoV-2 rewires cellular machinery to its advantage. By depleting PI4P and activating ATM in the cytoplasm, the virus creates an environment conducive to its replication while disrupting the host cell's normal functions. These findings highlight the potential of ATM inhibitors as a dual-purpose therapy, offering both antiviral and anti-inflammatory benefits.
 
The implications extend beyond COVID-19, suggesting that the mechanisms uncovered here could be relevant for other coronaviruses. This opens new avenues for developing broad-spectrum antiviral therapies, particularly those targeting lipid transport systems and the DDR pathways.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2024.12.05.626967v1
 
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