The HIV-1 Tat protein is monomethylated at lysine 71 by the lysine methyltransferase KMT7

Ibraheem Ali; Holly Ramage; Daniela Boehm; Lynnette M.A. Dirk; Naoki Sakane; Kazuki Hanada; Sara Pagans; Katrin Kaehlcke; Katherine Aull; Leor Weinberger; Raymond Trievel; Martina Schnoelzer; Masafumi Kamada; Robert Houtz; Melanie Ott

doi:10.1074/jbc.M116.735415

The HIV-1 Tat protein is monomethylated at lysine 71 by the lysine methyltransferase KMT7

Ibraheem Ali, Holly Ramage, Daniela Boehm, Lynnette M.A. Dirk, Naoki Sakane, Kazuki Hanada, Sara Pagans, Katrin Kaehlcke, Katherine Aull, Leor Weinberger, Raymond Trievel, Martina Schnoelzer, Masafumi Kamada, Robert Houtz, Melanie Ott

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Abstract

The HIV-1 transactivator protein Tat is a critical regulator of HIV transcription primarily enabling efficient elongation of viral transcripts. Its interactions with RNA and various host factors are regulated by ordered, transient post-translational modifications. Here, we report a novel Tat modification, monomethylation at lysine 71(K71). We found that Lys-71 monomethylation (K71me) is catalyzed by KMT7, a methyltransferase that also targets lysine 51 (K51) in Tat. Using mass spectrometry, in vitro enzymology, and modification-specific antibodies, we found that KMT7 monomethylates both Lys-71 and Lys-51 in Tat. K71me is important for full Tat transactivation, as KMT7 knockdown impaired the transcriptional activity of wild type (WT) Tat but not a Tat K71R mutant. These findings underscore the role of KMT7 as an important monomethyltransferase regulating HIV transcription through Tat.

Original language	English
Pages (from-to)	16240-16248
Number of pages	9
Journal	Journal of Biological Chemistry
Volume	291
Issue number	31
DOIs	https://doi.org/10.1074/jbc.M116.735415
State	Published - Jul 29 2016

Bibliographical note

Funding Information:
This work was supported by the University of California San Francisco, Gladstone Institute of Virology and Immunology Center for AIDS Research, a collaboration with JT Pharma, Gladstone Institutes, CA AIDS Research Program, and Grants R01AI083139, U19AI096113, T32IA7334-26, and P30AI027763 from the National Institutes of Health, and Grant ID F13-GI-316 from the California HIV/AIDS Research Program (CHRP). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank members of the Ott, Weinberger, and Verdin laboratories for helpful discussions, reagents, and expertise. We thank John Carroll for graphics, Stephen Ordway for editorial support, and Veronica Fonseca for administrative assistance.

Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

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10.1074/jbc.M116.735415

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Ali, I., Ramage, H., Boehm, D., Dirk, L. M. A., Sakane, N., Hanada, K., Pagans, S., Kaehlcke, K., Aull, K., Weinberger, L., Trievel, R., Schnoelzer, M., Kamada, M., Houtz, R., & Ott, M. (2016). The HIV-1 Tat protein is monomethylated at lysine 71 by the lysine methyltransferase KMT7. Journal of Biological Chemistry, 291(31), 16240-16248. https://doi.org/10.1074/jbc.M116.735415

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title = "The HIV-1 Tat protein is monomethylated at lysine 71 by the lysine methyltransferase KMT7",

abstract = "The HIV-1 transactivator protein Tat is a critical regulator of HIV transcription primarily enabling efficient elongation of viral transcripts. Its interactions with RNA and various host factors are regulated by ordered, transient post-translational modifications. Here, we report a novel Tat modification, monomethylation at lysine 71(K71). We found that Lys-71 monomethylation (K71me) is catalyzed by KMT7, a methyltransferase that also targets lysine 51 (K51) in Tat. Using mass spectrometry, in vitro enzymology, and modification-specific antibodies, we found that KMT7 monomethylates both Lys-71 and Lys-51 in Tat. K71me is important for full Tat transactivation, as KMT7 knockdown impaired the transcriptional activity of wild type (WT) Tat but not a Tat K71R mutant. These findings underscore the role of KMT7 as an important monomethyltransferase regulating HIV transcription through Tat.",

author = "Ibraheem Ali and Holly Ramage and Daniela Boehm and Dirk, {Lynnette M.A.} and Naoki Sakane and Kazuki Hanada and Sara Pagans and Katrin Kaehlcke and Katherine Aull and Leor Weinberger and Raymond Trievel and Martina Schnoelzer and Masafumi Kamada and Robert Houtz and Melanie Ott",

note = "Funding Information: This work was supported by the University of California San Francisco, Gladstone Institute of Virology and Immunology Center for AIDS Research, a collaboration with JT Pharma, Gladstone Institutes, CA AIDS Research Program, and Grants R01AI083139, U19AI096113, T32IA7334-26, and P30AI027763 from the National Institutes of Health, and Grant ID F13-GI-316 from the California HIV/AIDS Research Program (CHRP). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank members of the Ott, Weinberger, and Verdin laboratories for helpful discussions, reagents, and expertise. We thank John Carroll for graphics, Stephen Ordway for editorial support, and Veronica Fonseca for administrative assistance. Publisher Copyright: {\textcopyright} 2016 by The American Society for Biochemistry and Molecular Biology, Inc.",

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Ali, I, Ramage, H, Boehm, D, Dirk, LMA, Sakane, N, Hanada, K, Pagans, S, Kaehlcke, K, Aull, K, Weinberger, L, Trievel, R, Schnoelzer, M, Kamada, M, Houtz, R & Ott, M 2016, 'The HIV-1 Tat protein is monomethylated at lysine 71 by the lysine methyltransferase KMT7', Journal of Biological Chemistry, vol. 291, no. 31, pp. 16240-16248. https://doi.org/10.1074/jbc.M116.735415

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T1 - The HIV-1 Tat protein is monomethylated at lysine 71 by the lysine methyltransferase KMT7

AU - Ali, Ibraheem

AU - Ramage, Holly

AU - Boehm, Daniela

AU - Dirk, Lynnette M.A.

AU - Sakane, Naoki

AU - Hanada, Kazuki

AU - Pagans, Sara

AU - Kaehlcke, Katrin

AU - Aull, Katherine

AU - Weinberger, Leor

AU - Trievel, Raymond

AU - Schnoelzer, Martina

AU - Kamada, Masafumi

AU - Houtz, Robert

AU - Ott, Melanie

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PY - 2016/7/29

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N2 - The HIV-1 transactivator protein Tat is a critical regulator of HIV transcription primarily enabling efficient elongation of viral transcripts. Its interactions with RNA and various host factors are regulated by ordered, transient post-translational modifications. Here, we report a novel Tat modification, monomethylation at lysine 71(K71). We found that Lys-71 monomethylation (K71me) is catalyzed by KMT7, a methyltransferase that also targets lysine 51 (K51) in Tat. Using mass spectrometry, in vitro enzymology, and modification-specific antibodies, we found that KMT7 monomethylates both Lys-71 and Lys-51 in Tat. K71me is important for full Tat transactivation, as KMT7 knockdown impaired the transcriptional activity of wild type (WT) Tat but not a Tat K71R mutant. These findings underscore the role of KMT7 as an important monomethyltransferase regulating HIV transcription through Tat.

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The HIV-1 Tat protein is monomethylated at lysine 71 by the lysine methyltransferase KMT7

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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