期刊
NATURE MICROBIOLOGY
卷 4, 期 9, 页码 1532-1544出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41564-019-0460-3
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资金
- Agency for Medical Research and Development (AMED) [JP16gm0410017, 18fk0410014h0001, JP18fm0208006h002, JP18fk0410019h0001, JP18fk0410014h0001]
- Japan Society for the Promotion of Science (JSPS) KAKENHI [18H05278, 16H06429, 16K21723, 17H05813, 18H02662]
- Joint Usage/Research Center Program of the Institute for Frontier Life and Medical Sciences Kyoto University
- Takeda Science Foundation
- Uehara Memorial Foundation
- DFG priority programme 'Innate Sensing and Restriction of Retroviruses' [SPP 1923]
- state Baden-Wuerttemberg
- DFG [CRC 1279]
- Advanced ERC grant (Anti-Virome)
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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