2. Academic Validation
  3. N4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation

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

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. [email protected].
  • 12 Laboratory of Infection and Prevention, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan. [email protected].
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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