PKM2 induces mitophagy through the AMPK-mTOR pathway promoting CSFV proliferation
Viruses exploit the host cell's energy metabolism system to support their replication. Mitochondria, known as the powerhouse of the cell, play a critical role in regulating cell survival and virus replication. Our prior research indicated that the classical swine fever virus (CSFV) alters mitochondrial dynamics and triggers glycolytic metabolic reprogramming. However, the role and mechanism of PKM2, a key regulatory enzyme of glycolytic metabolism, in CSFV replication remain unclear. In this study, we discovered that CSFV enhances PKM2 expression and utilizes PKM2 to inhibit pyruvate production. Using an affinity purification coupled mass spectrometry system, we successfully identified PKM as a novel interaction partner of the CSFV non-structural protein NS4A. Furthermore, we validated the interaction between PKM2 and both CSFV NS4A and NS5A through co-immunoprecipitation and confocal analysis. PKM2 was found to promote the expression of both NS4A and NS5A. Moreover, we observed that PKM2 induces mitophagy by activating the AMPK-mTOR signaling pathway, thereby facilitating CSFV proliferation. In summary, our data reveal a novel mechanism whereby PKM2, a metabolic enzyme, promotes CSFV proliferation by inducing mitophagy. These findings offer a new avenue for developing antiviral strategies.
IMPORTANCE: Viruses rely on the host cell's material-energy metabolic system for replication, inducing host metabolic disorders and subsequent immunosuppression-a major contributor to persistent viral infections. Classical swine fever virus (CSFV) is no exception. Classical swine fever is a severe acute infectious disease caused by CSFV, resulting in significant economic losses to the global pig industry. While the role of the metabolic enzyme PKM2 (pyruvate dehydrogenase) in the glycolytic pathway of tumor cells has been extensively studied, its involvement in viral infection remains relatively unknown. Our data unveil a new mechanism by which the metabolic enzyme PKM2 mediates CSFV infection, offering novel avenues for the development of antiviral strategies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:98 |
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| Enthalten in: |
Journal of virology - 98(2024), 3 vom: 19. März, Seite e0175123 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Xiaodi [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 20.03.2024 Date Revised 27.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1128/jvi.01751-23 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM368083764 |
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| 100 | 1 | |a Liu, Xiaodi |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a PKM2 induces mitophagy through the AMPK-mTOR pathway promoting CSFV proliferation |
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| 500 | |a Date Revised 27.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Viruses exploit the host cell's energy metabolism system to support their replication. Mitochondria, known as the powerhouse of the cell, play a critical role in regulating cell survival and virus replication. Our prior research indicated that the classical swine fever virus (CSFV) alters mitochondrial dynamics and triggers glycolytic metabolic reprogramming. However, the role and mechanism of PKM2, a key regulatory enzyme of glycolytic metabolism, in CSFV replication remain unclear. In this study, we discovered that CSFV enhances PKM2 expression and utilizes PKM2 to inhibit pyruvate production. Using an affinity purification coupled mass spectrometry system, we successfully identified PKM as a novel interaction partner of the CSFV non-structural protein NS4A. Furthermore, we validated the interaction between PKM2 and both CSFV NS4A and NS5A through co-immunoprecipitation and confocal analysis. PKM2 was found to promote the expression of both NS4A and NS5A. Moreover, we observed that PKM2 induces mitophagy by activating the AMPK-mTOR signaling pathway, thereby facilitating CSFV proliferation. In summary, our data reveal a novel mechanism whereby PKM2, a metabolic enzyme, promotes CSFV proliferation by inducing mitophagy. These findings offer a new avenue for developing antiviral strategies | ||
| 520 | |a IMPORTANCE: Viruses rely on the host cell's material-energy metabolic system for replication, inducing host metabolic disorders and subsequent immunosuppression-a major contributor to persistent viral infections. Classical swine fever virus (CSFV) is no exception. Classical swine fever is a severe acute infectious disease caused by CSFV, resulting in significant economic losses to the global pig industry. While the role of the metabolic enzyme PKM2 (pyruvate dehydrogenase) in the glycolytic pathway of tumor cells has been extensively studied, its involvement in viral infection remains relatively unknown. Our data unveil a new mechanism by which the metabolic enzyme PKM2 mediates CSFV infection, offering novel avenues for the development of antiviral strategies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a AMPK-mTOR | |
| 650 | 4 | |a cellular metabolism | |
| 650 | 4 | |a classical swine fever virus | |
| 650 | 4 | |a mitophagy | |
| 650 | 4 | |a pyruvate kinase M2 | |
| 650 | 4 | |a viral infection | |
| 650 | 7 | |a AMP-Activated Protein Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.31 |2 NLM | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a NS4A protein, flavivirus |2 NLM | |
| 650 | 7 | |a Pyruvate Kinase |2 NLM | |
| 650 | 7 | |a EC 2.7.1.40 |2 NLM | |
| 650 | 7 | |a Pyruvates |2 NLM | |
| 650 | 7 | |a TOR Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Viral Nonstructural Proteins |2 NLM | |
| 700 | 1 | |a Yan, Quanhui |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xueyi |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Wenkang |e verfasserin |4 aut | |
| 700 | 1 | |a Zou, Linke |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Feifan |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Sen |e verfasserin |4 aut | |
| 700 | 1 | |a Yi, Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Hongxing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Mingqiu |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jinding |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Shuangqi |e verfasserin |4 aut | |
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