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TRIM5 is an innate immune sensor for the retrovirus capsid lattice

Abstract

TRIM5 is a RING domain-E3 ubiquitin ligase that restricts infection by human immunodeficiency virus (HIV)-1 and other retroviruses immediately following virus invasion of the target cell cytoplasm1,2. Antiviral potency correlates with TRIM5 avidity for the retrovirion capsid lattice3,4 and several reports indicate that TRIM5 has a role in signal transduction5,6,7, but the precise mechanism of restriction is unknown8. Here we demonstrate that TRIM5 promotes innate immune signalling and that this activity is amplified by retroviral infection and interaction with the capsid lattice. Acting with the heterodimeric, ubiquitin-conjugating enzyme UBC13–UEV1A (also known as UBE2N–UBE2V1), TRIM5 catalyses the synthesis of unattached K63-linked ubiquitin chains that activate the TAK1 (also known as MAP3K7) kinase complex and stimulate AP-1 and NFκB signalling. Interaction with the HIV-1 capsid lattice greatly enhances the UBC13–UEV1A-dependent E3 activity of TRIM5 and challenge with retroviruses induces the transcription of AP-1 and NF-κB-dependent factors with a magnitude that tracks with TRIM5 avidity for the invading capsid. Finally, TAK1 and UBC13–UEV1A contribute to capsid-specific restriction by TRIM5. Thus, the retroviral restriction factor TRIM5 has two additional activities that are linked to restriction: it constitutively promotes innate immune signalling and it acts as a pattern recognition receptor specific for the retrovirus capsid lattice.

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Figure 1: TRIM5 promotes innate immune signalling.
Figure 2: The TAK1 kinase complex interacts biochemically and functionally with TRIM5.
Figure 3: TRIM5 acts with UBC13–UEV1A to synthesize free K63-linked Ub chains that activate TAK1.
Figure 4: Retrovirus capsid sensing by TRIM5.

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Acknowledgements

We thank D. Baltimore, M. J. Birrer, J. Brojatsch, A. Cimarelli, A. DeIaco, S. Elledge, M. Emerman, W. Ferlin, D. Garcin, S. Ghosh, O. Haller, T. Hatziioannou, J. Hiscott, A. Iwasaki, D. Kolakofsky, M. Kosco-Vilbois, H. Malik, R. Medzhitov, M. R. Neagu, G. Napolitani, P. Palese, D. Pinschewer, O. Pornillos, L. Roux, O. Schwartz, M. Strubin, V. Studer, W. Sundquist, G. Towers, D. Trono, J. Tschopp, M. Yeager, M. Zufferey, and the Functional Genomics Center (Zürich), for ideas, technical assistance, and reagents. This work was supported by NIH grant RO1AI59159 to J.L., NIH grant R21AI087467 to W.M., Swiss National Science Foundation grant 3100A0-128655 to J.L. and 3100A0-122342 to M.G. and UZH Forschungskredit 54041402 to S.Z.

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Contributions

T.P., S.H., J.G., C.R., C.S., M.P., W.M., M.G.G. and J.L. designed the experiments; T.P., S.H., D.M., S.Z., J.G., J.La., C.R., F.A.S., M.P., A.B., P.D.U. and L.C. performed the experiments. All authors contributed to the assembly and writing of the manuscript.

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Correspondence to Jeremy Luban.

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The authors declare no competing financial interests.

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Pertel, T., Hausmann, S., Morger, D. et al. TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature 472, 361–365 (2011). https://doi.org/10.1038/nature09976

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