Elucidation of SAMHD1-independent function of HIV/SIV Vpx

• Project/Area Number: 25460570
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: Kumamoto University
• Principal Investigator: Fujita Mikako 熊本大学, 薬学部, 准教授 (00322256)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: HIV-2 / Vpx / SAMHD1 / 抗ウイルス宿主因子 / 変異体解析 / ポリプロリンモチーフ / 亜鉛フィンガー / マクロファージ / ポリプロリン / 蛋白質安定性 / 蛋白質発現 / 蛋白質分解 / ウイルス / 蛋白質 / 感染症 / HIV / 変異体

Outline of Final Research Achievements

HIV-2 Vpx has a function to degrade host anti-viral factor SAMHD1 in macrophages. We already showed SAMHD1 degradation-independent function in activated T cells, however the details remain elusive. This study was started to aim at elucidation of this function of Vpx. We first performed mutational analysis. As results, we found two mutants, C87A and P109A as candidates to have decreased SAMHD1 degradation-independent function, thus their details were examined. Finally, we got the following results: (1) C87 and the other three amino acids form zinc finger to stabilize protein. (2) poly-proline motif including P109 has various functions, e.g., to multimerize Vpx and regulate SAMHD1 degradation negatively, and to facilitate the specific degradation of SAMHD1 in macrophages. (3) There are no evidences that Vpx carries SAMHD1 degradation-independent function in macrophages. It can be considered that Vpx has this function in activated T cells, thus the detail is under the progress.

Research Products

• [Journal Article] Synthesis of the biotinylated anti-HIV compound BMMP and the target identification study. (2016)
  • Author(s): Kamo M, Tateishi H, Koga R, Okamoto Y, Otsuka M, Fujita M.
  • Journal Title: Bioorg. Med. Chem. Volume: 26 Issue: 1 Pages: 43-45
  • DOI: 10.1016/j.bmcl.2015.11.036
  • Peer Reviewed
• [Journal Article] Commentary: MARCH8 Inhibits HIV-1 Infection by Reducing Virion Incorporation of Envelopes Glycoproteins. (2016)
  • Author(s): Fujita M
  • Journal Title: Front. Microbiol. Volume: 7 Pages: 254-254
  • DOI: 10.3389/fmicb.2016.00254
  • NAID: 120006697194
  • Peer Reviewed / Open Access
• [Journal Article] l-Histidyl-glycyl-glycyl-l-histidine. Amono-acid structuring of the bleomycin-type pentadentate metal-binding environment capable of efficient double-strand cleavage of plasmid DNA. (2015)
  • Author(s): Ida S, Iwamaru K, Fujita M, Okamoto Y, Kudo Y, Kurosaki H, Otsuka M
  • Journal Title: Bioorg. Chem. Volume: 62 Pages: 8-14
  • Peer Reviewed
• [Journal Article] Novel metal chelating molecules with anticancer activity. Striking effect of the imidazole substitution of the histidine-pyridine-histidine system (2015)
  • Author(s): Ali, Taha F. S.; Iwamaru, Kana; Ciftci, Halil Ibrahim; Koga, Ryoko; Matsumoto, Masahiro; Oba, Yasunori; Kurosaki, Hiromasa; Fujita, Mikako; Okamoto, Yoshinari; Otsuka, Masami et. al.
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 23 Issue: 17 Pages: 5476-5482
  • DOI: 10.1016/j.bmc.2015.07.044
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Synthesis and Evaluation of New Pyrazoline Derivatives as Potential Anticancer Agents. (2015)
  • Author(s): Karabacak M, Altintop MD, Ciftci H, Koga R, Otsuka M, Fujita M, Ozdemir A.
  • Journal Title: Molecules Volume: 20 Issue: 10 Pages: 19066-19084
  • DOI: 10.3390/molecules201019066
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mutational analysis of HIV-2 Vpx shows that residue 109 in the poly-proline motif regulates degradation of SAMHD1 (2015)
  • Author(s): Halil Ibrahim Ciftci, Haruna Fujino, Ryoko Koga, Minami Yamamoto, Sogo Kawamura, Hiroshi Tateishi, Yasumasa Iwatani, Masami Otsuka, Mikako Fujita
  • Journal Title: FEBS Letters Volume: 未定 Issue: 13 Pages: 1505-1514
  • DOI: 10.1016/j.febslet.2015.04.038
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] A PI(4,5)P2 analog suppresses HIV-1 release and locked-in viral protein (2016)
  • Author(s): Hiroshi Tateishi, Kazuaki Monde, Ryoko Koga, Yuya Hayashi, Taishi Higashi, Keiichi Motoyama, Hidetoshi Arima, Kensaku Anraku, Masami Otsuka, Mikako Fujita
  • Organizer: Cold Spring Harbor Meeting, Retroviruses, 2016
  • Place of Presentation: Cold Spring Harbor, NY, USA
  • Year and Date: 2016-05-23
  • Int'l Joint Research
• [Presentation] Synthesis and applications of biotinylated zinc binding SN1 (2016)
  • Author(s): Mohamed Radwan, Ryoko Koga, Yoshinari Okamoto, Mikako Fujita, Masami Otsuka
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-03-26
• [Presentation] 抗HIV剤BMMPの作用機序解明と活性改良 (2016)
  • Author(s): 加茂真宏、立石大、山本充奈美、岡本良成、森川裕子、大塚雅巳、藤田美歌子
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-03-26
• [Presentation] Gag蛋白質を標的とした細胞死誘導型新規抗HIV薬の開発研究 (2016)
  • Author(s): 立石大、門出和精、村尾直樹、古賀涼子、林祐也、東大志、本山敬一、有馬英俊、安楽健作、藤田美歌子、大塚雅巳
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-03-26
• [Presentation] SAMHD1分解によるHIV-2 Vpx C末端ポリプロリンモチーフの役割 (2015)
  • Author(s): 藤田美歌子、Halil Ciftci Ibrahim, 藤野悠那、古賀涼子、山本充奈美、大塚雅巳
  • Organizer: 第29回日本エイズ学会学術集会
  • Place of Presentation: 東京ドームホテル
  • Year and Date: 2015-11-30
• [Presentation] Elucidation of action mechanism of BMMP and synthesis of derivatives to improve activity (2015)
  • Author(s): Masahiro Kamo, Hiroshi Tateishi, Minami Yamamoto, Yoshinari Okamoto, Yuko Morikawa, Shogo Misumi, Masami Otsuka, Mikako Fujita
  • Organizer: 第29回日本エイズ学会学術集会
  • Place of Presentation: 東京ドームホテル
  • Year and Date: 2015-11-30
• [Presentation] Pr55Gag蛋白質を標的とした新規抗HIV剤の開発研究 (2015)
  • Author(s): 立石大、門出和精、村尾直樹、古賀涼子、林祐也、東大志、本山敬一、有馬英俊、安楽健作、藤田美歌子、大塚雅巳
  • Organizer: 第33回メディシナルケミストリーシンポジウム
  • Place of Presentation: 幕張国際研修センター
  • Year and Date: 2015-11-25
• [Presentation] TRAF6ポリユビキチン化を抑制する低分子化合物によるシグナル伝達制御の検討 (2015)
  • Author(s): 古賀涼子、江島智彦、金丸陽亮、柴田祐里、田口祐、井上純一郎、大塚雅巳、藤田美歌子
  • Organizer: 第33回メディシナルケミストリーシンポジウム
  • Place of Presentation: 幕張国際研修センター
  • Year and Date: 2015-11-25
• [Presentation] Roles of zinc-binding motif of HIV-2 Vpx protein (2015)
  • Author(s): Minami Yamamoto, Haruna Fujino, Kazunori Shimagaki, Ryoko Koga, Ciftci Halil Ibrahim, Masami Otsuka Mikako Fujita
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2015-11-22
• [Presentation] New strategy to suppress HIV release by a PI(4,5)P2 mimic (2015)
  • Author(s): Mikako Fujita, Hiroshi Tateishi, Kazuaki Monde, Naoki Murao, Yuya Hayashi, Taishi Higashi, Keiichi Motoyama, Hidetoshi Arima, Kensaku Anraku, Masami Otsuka
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2015-11-22
• [Presentation] Roles of poly-proline motif of HIV-2 protein (2015)
  • Author(s): Halil Ibrahim Ciftci, Demirci Hasan, Haruna Fujino, Ryoko Koga, Minami Yamamoto, Masami Otsuka, Mikako Fujita
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2015-11-22
• [Presentation] Elucidation of action mechanism of BMMP and improvement of its activity by chemical modification (2015)
  • Author(s): Masahiro Kamo, Hiroshi Tateishi, Minami Yamamoto, Yoshinari Okamoto, Yuko Morikawa, Shogo Misumi, Masami Otsuka, Mikako Fujita
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2015-11-22
• [Presentation] Roles of the zinc finger and poly-proline motifs in HIV-2 Vpx protein (2015)
  • Author(s): Halil Ibrahim Ciftci, Haruna Fujino, Ryoko Koga, Minami Yamamoto, Masami Otsuka, Mikako Fujita,
  • Organizer: Cold Spring Harbor Meeting, Retroviruses, 2015
  • Place of Presentation: Cold Spring Harbor, NY, USA
  • Year and Date: 2015-05-18
  • Int'l Joint Research
• [Presentation] Development of a low molecular compound targetting TRAF6 protein (2015)
  • Author(s): Ryoko Koga, Tomohiko Ejima, Yosuke Kanemaru, Yuri Shibata, Yuu Taguchi, Jun-ichiro Inoue, Masami Otsuka, Mikako Fujita
  • Organizer: International Symposium on Chronic Inflammatory Diseases, Kumamoto
  • Place of Presentation: 熊本大学
  • Year and Date: 2015-05-16
  • Int'l Joint Research
• [Presentation] Mutational analysis of HIV-2 Vpx concerning on ability to degrade SAMHD1 (2014)
  • Author(s): Ciftci Halil Ibrahim、藤野悠那、古賀涼子、山本充奈美、川村宗吾、岩谷靖雅、大塚雅巳、藤田美歌子
  • Organizer: 第28回日本エイズ学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-12-04
• [Presentation] HIV-2 Vpxにおける亜鉛フィンガー、ポリプロリンモチーフの役割と翻訳後修飾の意義 (2014)
  • Author(s): 山本充奈美、古賀涼子、藤野悠那、Halil Ibrahim Ciftci、大塚雅巳、藤田美歌子
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-26
• [Presentation] HIV-2 Vpxにおける亜鉛フィンガーおよびC末端ポリプロリンモチーフの役割 (2014)
  • Author(s): 藤野悠那、山本充奈美、Halil Ibrahim Ciftci、島垣和功、古賀涼子、大塚雅巳、藤田美歌子
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10
• [Presentation] SAMHD1-independent functions of HIV-2 Vpx protein (2014)
  • Author(s): Mikako Fujita, Halil Ibrahim Ciftci, Minami Yamamoto, Haruna Fujino, Ryoko Koga, Sogo Kawamura, Yasumasa Iwatani, Masami Otsuka
  • Organizer: Cold Spring Harbor Laboratory Meeting, Retroviruses
  • Place of Presentation: Cold Spring Harbor, USA
  • Year and Date: 2014-05-20
• [Presentation] マクロファージにおけるSAMHD1非依存的なHIV-2 Vpxの機能 (2013)
  • Author(s): 山本充奈美、野間口雅子、古賀涼子、岩谷靖雅、高宗暢暁、三隅将吾、大塚雅巳、足立昭夫、藤田美歌子
  • Organizer: 第６１回日本ウイルス学会学術集会
  • Place of Presentation: 神戸国際会議場
• [Presentation] HIV-2 Vpx蛋白質の多量化の解析 (2013)
  • Author(s): 藤野悠那、古賀涼子、大塚雅巳、藤田美歌子
  • Organizer: 第６１回日本ウイルス学会学術集会
  • Place of Presentation: 神戸国際会議場
• [Presentation] SAMHD1-independent function of HIV-2 Vpx protein (2013)
  • Author(s): チッフチハリルイブラヒム、古賀涼子、岩谷靖雅、野間口雅子、足立昭夫、大塚雅巳、藤田美歌子
  • Organizer: 第２７回日本エイズ学会学術集会
  • Place of Presentation: 崇城大学ホール
• [Remarks]
  • URL: http://www.pharm.kumamoto-u.ac.jp/Labs/bunsigouseiHP/