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* Protein Chemistry Research Group, Institute of Biotechnology, University of Helsinki, Helsinki, Finland; and
Unit of Excellence in Immunotoxicology, Finnish Institute of Occupational Health, Helsinki, Finland
Influenza A virus is one of the most important causes of respiratory infection. During viral infection, multiple cell signaling cascades are activated, resulting in the production of antiviral cytokines and initiation of programmed cell death of virus-infected cells. In the present study, we have used subcellular proteomics to reveal the host response to influenza A infection at the protein level in human macrophages. Macrophages were infected with influenza A virus, after which the cytosolic and mitochondrial cell fractions were prepared and analyzed by using two-dimensional electrophoresis for protein separation and mass spectrometry for protein identification. In cytosolic proteomes, the level of several heat shock proteins and fragments of cytoskeletal proteins was clearly up-regulated during influenza A virus infection. In mitochondrial proteomes, simultaneously with the expression of viral proteins, the level of intact actin and tubulin was highly up-regulated. This was followed by translocation of the components of antiviral RNA recognition machinery, including RIG-I (retinoic acid-inducible protein I), TRADD (TNFR1-associated death domain protein), TRIM25 (tripartite motif protein 25), and IKK
(inducible I
B kinase), onto the mitochondria. Cytochalasin D, a potent inhibitor of actin polymerization, clearly inhibited influenza A virus-induced expression of IFN-β, IL-29, and TNF-
, suggesting that intact actin cytoskeleton structure is crucial for proper activation of antiviral response. At late phases of infection mitochondrial fragmentation of actin was seen, indicating that actin fragments, fractins, are involved in disruption of mitochondrial membranes during apoptosis of virus-infected cells. In conclusion, our results suggest that actin network interacts with mitochondria to regulate both antiviral and cell death signals during influenza A virus infection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Academy of Finland Grant 114437 and the Sigrid Jusélius Foundation.
2 Address correspondence and reprint requests to Dr. Tuula Nyman, Protein Chemistry Research Group, Institute of Biotechnology, P.O. Box 65, FI-00014, University of Helsinki, Helskinki, Finland. E-mail address: tuula.nyman{at}helsinki.fi
3 Abbreviations used in this paper: PRR, pattern recognition receptor; IKK, inducible IB kinase; BiP, heat shock 70-kDa protein 5, GRP78; GRP, glucose-regulated protein; HSP, heat shock protein; IRF-3, IFN regulator factor 3; MAVS, mitochondrial antiviral signaling protein; NTC, no template control; PMF, peptide mass fingerprint; RIG-I, retinoic acid-inducible protein I; TRADD, TNFR1-associated death domain protein; TRIM25, tripartite motif protein 25; 2-DE, two-dimensional electrophoresis; XIAP, X-linked inhibitor of apoptosis.
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  Y. Espanol, D. Thut, A. Schneider, and L. R. de Pouplana A mechanism for functional segregation of mitochondrial and cytosolic genetic codes PNAS, November 17, 2009; 106(46): 19420 - 19425. [Abstract] [Full Text] [PDF]
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