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Novel molecular mechanism of influenza virus-induced inflammatory responses

Clues for developing new vaccines and anti-inflammatory drugs

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Institute of Medical Science
2013/10/25

Associate Professor Takeshi Ichinohe at the Institute of Medical Science, the University of Tokyo, and his collaborators in Kyushu University have demonstrated that a mitochondrial outer membrane protein mitofusin 2 is required for influenza virus-induced NLRP3 inflammasome activation.

© Takeshi Ichinohe, Influenza virus infection activates the NLRP3 and stimulates association between mitofusin 2 (Mfn2) and NLRP3. This leads to recruitment of adaptor protein ASC and immature form of caspase-1 (pro-caspase-1) to form the NLRP3 inflammasome. Then, active caspase-1 cleaves the precursor form of IL-1β and IL-18 and stimulates their secretion. OM, outer membrane; IM, inner membrane.

When a small piece of matter enters the nose nothing happens, but when an influenza virus infects the cells of the nasal membrane we develop a fever. This is because the cells of the nasal membrane can detect the presence of the virus. This means that the cells of our body are able to differentiate between a virus and a piece of matter too small to be seen by the eye. Ichinohe and his colleagues have previously demonstrated that influenza the M2 protein activates the NLRP3 inflammasome and the inflammasomes-dependent IL-1β secretion in the lung of mice, which is required for influenza virus-specific adaptive immune responses. However, the precise mechanism by which the NLRP3 is activated in virus-infected cells is not well understood. Now, they have shown that the mitochondrial membrane potential-dependent association between NLRP3 and a mitochondrial outer membrane protein mitofusin 2, a mediator of mitochondrial fusion, is required for influenza virus-induced IL-1β secretion. These results highlight the importance of mitochondria as a platform of influenza virus-induced inflammatory responses.

These results provide clues for developing new vaccines and anti-inflammatory drugs. This study has been published in Proceedings of the National Academy of Sciences of the United States of America (online on October 14 EST)

Press release [pdf] (Japanese)

Paper

Takeshi Ichinohe, Tatsuya Yamazaki, Takumi Koshiba, Yusuke Yanagi,
“Mitochondrial protein mitofusin 2 is required for NLRP3 inflammasome activation after RNA virus infection”,
Proceedings of the National Academy of Sciences
Online Edition: 2013/10/14 (Japan time), doi: 10.1073/pnas.1312571110.
Article link

Links

The Institute of Medical Science

Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science

Ichinohe Laboratory, Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science (Japanese)

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