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Virus-infection or 5'ppp-RNA activates antiviral signal through redistribution of IPS-1 mediated by MFN1.

Onoguchi K, Onomoto K, Takamatsu S, Jogi M, Takemura A, Morimoto S, Julkunen I, Namiki H, Yoneyama M, Fujita T - PLoS Pathog. (2010)

Bottom Line: In doing so we discovered that viral infection as well as transfection with 5'ppp-RNA resulted in the redistribution of IPS-1 to form speckle-like aggregates in cells.We further found that Mitofusin 1 (MFN1), a key regulator of mitochondrial fusion and a protein associated with IPS-1 on the outer membrane of mitochondria, positively regulates RLR-mediated innate antiviral responses.Our study suggests that mitochondria participate in the segregation of IPS-1 through their fusion processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan.

ABSTRACT
In virus-infected cells, RIG-I-like receptor (RLR) recognizes cytoplasmic viral RNA and triggers innate immune responses including production of type I and III interferon (IFN) and the subsequent expression of IFN-inducible genes. Interferon-beta promoter stimulator 1 (IPS-1, also known as MAVS, VISA and Cardif) is a downstream molecule of RLR and is expressed on the outer membrane of mitochondria. While it is known that the location of IPS-1 is essential to its function, its underlying mechanism is unknown. Our aim in this study was to delineate the function of mitochondria so as to identify more precisely its role in innate immunity. In doing so we discovered that viral infection as well as transfection with 5'ppp-RNA resulted in the redistribution of IPS-1 to form speckle-like aggregates in cells. We further found that Mitofusin 1 (MFN1), a key regulator of mitochondrial fusion and a protein associated with IPS-1 on the outer membrane of mitochondria, positively regulates RLR-mediated innate antiviral responses. Conversely, specific knockdown of MFN1 abrogates both the virus-induced redistribution of IPS-1 and IFN production. Our study suggests that mitochondria participate in the segregation of IPS-1 through their fusion processes.

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IPS-1 interacts with MFN1 and MFN2.IPS-1-HeLa cells were infected with NDV for 12 h, and then FLAG-IPS-1 was immunoprecipitated with anti-FLAG antibody. Co-immunoprecipitated MFN1 and MFN2 were detected by anti-MFN1 antibody and anti-MFN2 antibody, respectively. Neither OPA1 nor DRP1 was co-immunoprecipitated with FLAG-IPS-1. Mitochondrial protein BCL-Xl was used as a control and was also examined by anti-BCLXl antibody.
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ppat-1001012-g010: IPS-1 interacts with MFN1 and MFN2.IPS-1-HeLa cells were infected with NDV for 12 h, and then FLAG-IPS-1 was immunoprecipitated with anti-FLAG antibody. Co-immunoprecipitated MFN1 and MFN2 were detected by anti-MFN1 antibody and anti-MFN2 antibody, respectively. Neither OPA1 nor DRP1 was co-immunoprecipitated with FLAG-IPS-1. Mitochondrial protein BCL-Xl was used as a control and was also examined by anti-BCLXl antibody.

Mentions: To explore the molecular mechanism of how IPS-1 is regulated by MFN1, co-immunoprecipitation was performed using cells stably expressing IPS-1. FLAG-IPS-1 was precipitated by anti-FLAG and the associated proteins were analyzed by immunoblotting (Fig. 10). Both MFN1 and MFN2 constitutively associated with IPS-1 in the cells, but an unrelated mitochondrial outer membrane protein, BCL-XL, did not associate with IPS-1. Furthermore, OPA1 and DRP1 did not co-immunoprecipitate with FLAG-IPS-1. These data suggest that IPS-1 selectively associates with MFN1 and MFN2.


Virus-infection or 5'ppp-RNA activates antiviral signal through redistribution of IPS-1 mediated by MFN1.

Onoguchi K, Onomoto K, Takamatsu S, Jogi M, Takemura A, Morimoto S, Julkunen I, Namiki H, Yoneyama M, Fujita T - PLoS Pathog. (2010)

IPS-1 interacts with MFN1 and MFN2.IPS-1-HeLa cells were infected with NDV for 12 h, and then FLAG-IPS-1 was immunoprecipitated with anti-FLAG antibody. Co-immunoprecipitated MFN1 and MFN2 were detected by anti-MFN1 antibody and anti-MFN2 antibody, respectively. Neither OPA1 nor DRP1 was co-immunoprecipitated with FLAG-IPS-1. Mitochondrial protein BCL-Xl was used as a control and was also examined by anti-BCLXl antibody.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908619&req=5

ppat-1001012-g010: IPS-1 interacts with MFN1 and MFN2.IPS-1-HeLa cells were infected with NDV for 12 h, and then FLAG-IPS-1 was immunoprecipitated with anti-FLAG antibody. Co-immunoprecipitated MFN1 and MFN2 were detected by anti-MFN1 antibody and anti-MFN2 antibody, respectively. Neither OPA1 nor DRP1 was co-immunoprecipitated with FLAG-IPS-1. Mitochondrial protein BCL-Xl was used as a control and was also examined by anti-BCLXl antibody.
Mentions: To explore the molecular mechanism of how IPS-1 is regulated by MFN1, co-immunoprecipitation was performed using cells stably expressing IPS-1. FLAG-IPS-1 was precipitated by anti-FLAG and the associated proteins were analyzed by immunoblotting (Fig. 10). Both MFN1 and MFN2 constitutively associated with IPS-1 in the cells, but an unrelated mitochondrial outer membrane protein, BCL-XL, did not associate with IPS-1. Furthermore, OPA1 and DRP1 did not co-immunoprecipitate with FLAG-IPS-1. These data suggest that IPS-1 selectively associates with MFN1 and MFN2.

Bottom Line: In doing so we discovered that viral infection as well as transfection with 5'ppp-RNA resulted in the redistribution of IPS-1 to form speckle-like aggregates in cells.We further found that Mitofusin 1 (MFN1), a key regulator of mitochondrial fusion and a protein associated with IPS-1 on the outer membrane of mitochondria, positively regulates RLR-mediated innate antiviral responses.Our study suggests that mitochondria participate in the segregation of IPS-1 through their fusion processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan.

ABSTRACT
In virus-infected cells, RIG-I-like receptor (RLR) recognizes cytoplasmic viral RNA and triggers innate immune responses including production of type I and III interferon (IFN) and the subsequent expression of IFN-inducible genes. Interferon-beta promoter stimulator 1 (IPS-1, also known as MAVS, VISA and Cardif) is a downstream molecule of RLR and is expressed on the outer membrane of mitochondria. While it is known that the location of IPS-1 is essential to its function, its underlying mechanism is unknown. Our aim in this study was to delineate the function of mitochondria so as to identify more precisely its role in innate immunity. In doing so we discovered that viral infection as well as transfection with 5'ppp-RNA resulted in the redistribution of IPS-1 to form speckle-like aggregates in cells. We further found that Mitofusin 1 (MFN1), a key regulator of mitochondrial fusion and a protein associated with IPS-1 on the outer membrane of mitochondria, positively regulates RLR-mediated innate antiviral responses. Conversely, specific knockdown of MFN1 abrogates both the virus-induced redistribution of IPS-1 and IFN production. Our study suggests that mitochondria participate in the segregation of IPS-1 through their fusion processes.

Show MeSH
Related in: MedlinePlus