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. [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.