N4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation

Nat Microbiol. 2019 Sep;4(9):1532-1544. doi: 10.1038/s41564-019-0460-3.

Daichi Yamasoba ¹ ² ³, Kei Sato ⁴ ⁵ ⁶, Takuya Ichinose ¹ ² ³, Tomoko Imamura ², Lennart Koepke ⁷, Simone Joas ⁷, Elisabeth Reith ⁷, Dominik Hotter ⁷, Naoko Misawa ⁴, Kotaro Akaki ¹ ² ³, Takuya Uehata ¹ ², Takashi Mino ¹ ², Sho Miyamoto ⁸, Takeshi Noda ⁸, Akio Yamashita ⁹, Daron M Standley ¹⁰, Frank Kirchhoff ⁷, Daniel Sauter ⁷, Yoshio Koyanagi ⁴, Osamu Takeuchi ¹¹ ¹²

Affiliations

1 Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
2 Laboratory of Infection and Prevention, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
3 Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
4 Laboratory of Systems Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
5 CREST, Japan Science and Technology Agency, Saitama, Japan.
6 Department of Systems Virology, Institute for Medical Science, University of Tokyo, Tokyo, Japan.
7 Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
8 Laboratory of Ultrastructural Virology, Institute for Frontier Life and Medical Sciences, Kyoto, Japan.
9 Department of Molecular Biology, Yokohama City University School of Medicine, Kanagawa, Japan.
10 Department of Genome Informatics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
11 Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan. otake@mfour.med.kyoto-u.ac.jp.
12 Laboratory of Infection and Prevention, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan. otake@mfour.med.kyoto-u.ac.jp.

PMID: 31133753 DOI: 10.1038/s41564-019-0460-3

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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