Abstract
RNA-modulating factors not only regulate multiple steps of cellular RNA metabolism, but also emerge as key effectors of the immune response against invading viral pathogens including human immunodeficiency virus type-1 (HIV-1). However, the cellular RNA-binding proteins involved in the establishment and maintenance of latent HIV-1 reservoirs have not been extensively studied. Here, we screened a panel of 62 cellular RNA-binding proteins and identified NEDD4-binding protein 1 (N4BP1) as a potent interferon-inducible inhibitor of HIV-1 in primary T cells and macrophages. N4BP1 harbours a prototypical PilT N terminus-like RNase domain and inhibits HIV-1 replication by interacting with and degrading viral mRNA species. Following activation of CD4+ T cells, however, N4BP1 undergoes rapid cleavage at Arg 509 by the paracaspase named mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1). Mutational analyses and knockout studies revealed that MALT1-mediated inactivation of N4BP1 facilitates the reactivation of latent HIV-1 proviruses. Taken together, our findings demonstrate that the RNase N4BP1 is an efficient restriction factor of HIV-1 and suggest that inactivation of N4BP1 by induction of MALT1 activation might facilitate elimination of latent HIV-1 reservoirs.
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The data that support the findings of this study are available from the corresponding author upon request.
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Acknowledgements
We thank all colleagues in our laboratory for helpful discussions, M. Tsuji and J. Hasegawa for secretarial assistance, and R. Linsenmeyer and J. A. van der Merwe for excellent technical assistance. We thank K. Sutter (University of Duisburg-Essen, Germany) for providing IFN-α subtypes and C. Collins (UCSD, USA), B. Hahn (University of Pennsylvania, USA), W. C. Greene (Gladstone Institute for Virology and immunology, USA), D. N. Levy (New York University of Dentistry), H. Fan (UC Irvine, USA) and D. Russell (University of Washington, USA) for providing plasmids. This work was supported by the Agency for Medical Research and Development (AMED) under grant numbers JP16gm0410017 (to O.T.), 18fk0410014h0001 (to O.T.), JP18fm0208006h002 (to K.S.), JP18fk0410019h0001 (to K.S.) and JP18fk0410014h0001 (to Y.K.); the Japan Society for the Promotion of Science (JSPS) KAKENHI grant numbers 18H05278 (to O.T.), 16H06429 (to K.S.), 16K21723 (to K.S.), 17H05813 (to K.S.) and 18H02662 (to K.S.), the Joint Usage/Research Center Program of the Institute for Frontier Life and Medical Sciences Kyoto University (to O.T., K.S. and Y.K.); and the Core-to-Core Program. This work was also supported by grants from Takeda Science Foundation and The Uehara Memorial Foundation (to O.T.). D.S. was supported by the DFG priority programme ‘Innate Sensing and Restriction of Retroviruses’ (SPP 1923) and the junior professorship programme of the state Baden-Wuerttemberg. F.K. is also supported by SPP 1923, DFG CRC 1279 and an Advanced ERC grant (Anti-Virome).
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D.Y., K.S., D.S. and O.T. designed the study. D.Y. designed, carried out and analysed experiments. T. Ichinose, T. Imamura, L.K., S.J., E.R., D.H., N.M, K.A, T.U and T.M. provided technical and intellectual assistance. S.M. and T.N. conducted influenza infection experiments. A.Y. provided recombinant proteins. D.M.S. performed structural modelling and bioinformatic analysis. D.Y., D.S. and O.T. wrote the manuscript. K.S., F.K., Y.K. and O.T. supervised the study.
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Yamasoba, D., Sato, K., Ichinose, T. et al. N4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation. Nat Microbiol 4, 1532–1544 (2019). https://doi.org/10.1038/s41564-019-0460-3
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DOI: https://doi.org/10.1038/s41564-019-0460-3
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