Role of APOBEC deaminases in human tumor virus infection

• Project/Area Number: 26293103
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: Kanazawa University
• Principal Investigator: Muramatsu Masamichi 金沢大学, 医学系, 教授 (20359813)
• Co-Investigator(Renkei-kenkyūsha): KITAMURA Kouichi 金沢大学, 医学系, 助教 (70378892) ; WAKAE Kousho 金沢大学, 医学系, 助教 (70638303)
• Research Collaborator: KOURA Miki ; SIMADU Miyuki ; Que Lusheng ; Li Yingfang ; Mohiuddin Md ; Liu Guangyan ; Monjurul Ahasan ; Wang Zhe
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: APOBEC3 / AID / virus / hypermutation / Hepatitis B virus / Papillomavirus / B型肝炎ウイルス / 腫瘍ウイルス / APOBEC / 高頻度変異 / パピローマウイルス / 抗ウイルス活性 / ウイルス複製 / ウイルス / 発癌 / 子宮頸癌 / 抗ウイルス因子 / 宿主因子 / APOBECタンパク / Hypermutation / DNA損傷修復反応

Outline of Final Research Achievements

We investigated antiviral role of immune effecter molecules APOBEC in viral infection of papillomavirus (HPV) and hepatitis B virus (HBV). Experimental results suggest that APOBECs reduce infectivity of HPV16 pseudovirion by interfering viral assemble in vitro. DNA sequencing of clinical samples derived from precancerous cervixs revealed that APOBECs introduce hypermutation in HPV16 viral DNA. Mapping of mutation identifies viral promoter and replication origin as a hot spot of hypermutation mechanism. We also found that AID is induced in hepatocytes by TGFb stimulation and AID forms an RNP complex of viral P protein and host RNA exosome, resulting in degradation of HBV RNA. These studies demonstrate significant role of APOBEC protein in HPV and HBV infection.

Research Products

• [Int'l Joint Research] 大連大学附属中山医院/腫瘍科(中国)
• [Int'l Joint Research] Dalian University(中国)
• [Int'l Joint Research] Chinese Medical University(中国)
• [Journal Article] APOBEC3A Associates with Human Papillomavirus Genome Integration in Oropharyngeal Cancers (2017)
  • Author(s): Satoru Kondo, Kousho Wakae, Naohiro Wakisaka, Yosuke Nakanishi, Kazuya Ishikawa, Takeshi Komori, Makiko Moriyama-Kita, Kazuhira Endo, Shigeyuki Murono, Zhe Wang,, Kouichi Kitamura, Tomoaki Nishiyama, Katsushi Yamaguchi, Shuji Shigenobu, Masamichi Muramatsu, and Tomokazu Yoshizaki
  • Journal Title: Oncogene. Volume: 36 Issue: 12 Pages: 1687-1697
  • DOI: 10.1038/onc.2016.335
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel splenic B1 regulatory cell subset suppresses an allergic disease via PI3K-Akt pathway activation (2016)
  • Author(s): Matsushiba T, Le Huu D, Kobayashi T, Hamaguchi Y, Hasegawa M, Naka K, Hirao A, Muramatsu M, Takehara K, Fujimoto M
  • Journal Title: J Allergy Clin Immunol. Volume: 6749 Pages: 00130-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Expression of activation-induced cytidine deaminase enhances the clearance of pneumococcal pneumonia: evidence of a subpopulation of protective anti-pneumococcal B1a cells (2016)
  • Author(s): Yamamoto Natsuo, Kerfoot SM, Hutchinson AT, Dela Cruz CS, Nakazawa N, Szczepanik M, Majewska-Szczepanik M, Nazimek K, Ohana N, Bryniarski K, Mori T, Muramatsu M, Kanemitsu K, Askenase PW
  • Journal Title: Immunology Volume: 147 Issue: 1 Pages: 97-113
  • DOI: 10.1111/imm.12544
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel splenic B1 regulatory cell subset suppresses an allergic disease via PI3K-Akt pathway activation (2016)
  • Author(s): Matsushita T, Le Huu D, Kobayashi T, Hamaguchi Y, Hasegawa M, Naka K, Hirao A, Muramatsu M, Takehara K, Fujimoto M.
  • Journal Title: J Allergy Clin Immunol. Volume: In press
  • Peer Reviewed
• [Journal Article] TGF-β Suppression of HBV RNA through AID-dependent Recruitment of an RNA Exosome Complex (2015)
  • Author(s): Guoxin Liang, Guangyan Liu, Kouichi Kitamura, Zhe Wang, Sajeda Chowdhury, Ahasan Md Monjurul, Kousho Wakae, Miki Koura, Miyuki Shimadu, Kazuo Kinoshita, and Masamichi Muramatsu
  • Journal Title: PLoS Pathog /journal.ppat.1004780. eCollection 2015. Volume: 11(4)
  • NAID: 120005646683
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hypermutation in the E2 gene of human papillomavirus type 16 in cervical intraepithelial neoplasia. (2015)
  • Author(s): Kukimoto I, Mori S, Aoyama S, Wakae K, Muramatsu M, Kondo K.
  • Journal Title: Journal of Medical Virology Volume: 87 Issue: 10 Pages: 1754-1760
  • DOI: 10.1002/jmv.24215
  • Peer Reviewed
• [Journal Article] Genetic variations of human papillomavirus type 16: implications for cervical carcinogenesis. (総説) (2015)
  • Author(s): Kukimoto I, Muramatsu M.
  • Journal Title: Jpn J Infect Dis. Volume: 68(3) Pages: 169-175
  • Peer Reviewed
• [Journal Article] Detection of hypermutated human papillomavirus type 16 genome by Next-Generation Sequencing. (2015)
  • Author(s): Wakae K, Aoyama S, Wang Z, Kitamura K, Liu G, Monjurul AM, Koura M, Imayasu M, Sakamoto N, Nakamura M, Kyo S, Kondo S, Fujiwara H, Yoshizaki T, Kukimoto I, Yamaguchi K, Shigenobu S, Nishiyama T, Muramatsu M.
  • Journal Title: Virology. Volume: 485 Pages: 460-466
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Genetic Variations of Human Papillomavirus Type 16: Implications for Cervical Carcinogenesis. (2015)
  • Author(s): Kukimoto I, Muramatsu M.
  • Journal Title: Jpn J Infect Dis Volume: 印刷中
  • NAID: 130005070792
  • Peer Reviewed / Open Access
• [Journal Article] APOBEC3A and 3C decrease human papillomavirus 16 pseudovirion infectivity. (2015)
  • Author(s): Ahasan MM, Wakae K, Wang Z, Kitamura K, Liu G, Koura M, Imayasu M, Sakamoto N, Hanaoka K, Nakamura M, Kyo S, Kondo S, Fujiwara H, Yoshizaki T, Mori S, Kukimoto I, Muramatsu M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 457 Issue: 3 Pages: 295-9
  • DOI: 10.1016/j.bbrc.2014.12.103
  • Peer Reviewed / Open Access
• [Journal Article] Hypermutation in the E2 Gene of Human Papillomavirus Type 16 in Cervical Intraepithelial Neoplasia (2015)
  • Author(s): Iwao kukimoto, Seiichiro Mori, Satoru aoyama, Kosho Wakae, Masamichi Muramatsu, kazunari Kondo
  • Journal Title: Journal of Medical Virology Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] HPV Status Determines the Efficacy of Adjuvant Chemotherapy With S-1, an Oral Fluorouracil Prodrug, in Oropharyngeal Cancer. (2014)
  • Author(s): Wakisaka N, Yoshida S, Kondo S, Kita M, Endo K, Tsuji A, Murono S, Muramatsu M, Yoshizaki T
  • Journal Title: Ann Otol Rhinol Laryngol Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Immunoglobulin class switching to IgG4 in Warthin tumor and analysis of serum IgG4 levels and IgG4-positive plasma cells in the tumor. (2014)
  • Author(s): Aga M, Kondo S, Yamada K, Wakisaka N, Yagi-Nakanishi S, Tsuji A, Endo K, Murono S, Ito M, Muramatsu M, Kawano M, Yoshizaki T
  • Journal Title: Hum Pathol Volume: 45 Pages: 793-801
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Role of APOBEC proteins in HBV and HPV16 infections (2017)
  • Author(s): 村松 正道
  • Organizer: International Symposium on Immune Diversity and Cancer Therapy Kobe 2017
  • Place of Presentation: 神戸ポートピアホテル
  • Int'l Joint Research / Invited
• [Presentation] Flap endonuclease 1 is involved in the formation of HBV cccDNA (2016)
  • Author(s): Kouichi Kitamura , Kousho Wakae , Lusheng Que , Md Mohiuddin ,and Masamichi Muramatsu
  • Organizer: 2016 International HBV Meeting、Hepatitis B foundation
  • Place of Presentation: Yonsei University, Soul Korea
  • Year and Date: 2016-09-21
  • Int'l Joint Research
• [Presentation] APOBEC Deaminases: A new type of Antiviral Factor Masamichi Muramatsu (2016)
  • Author(s): 村松 正道
  • Organizer: BIT’s 7th Annual World DNA and Genome Day 2016
  • Place of Presentation: 中国大連国際会議センター
  • Int'l Joint Research / Invited
• [Presentation] B型肝炎ウイルスのcccDNA形成機序の研究 (2016)
  • Author(s): 喜多村晃一、若江亨祥、村松正道
  • Organizer: 平成２８年度 北陸腸内細菌研究会
  • Place of Presentation: ホテル日航金沢
• [Presentation] APOBECファミリーとその抗ウイルス活性 (2016)
  • Author(s): 村松正道
  • Organizer: 第13回ウイルス学キャンプ in 湯河原
  • Place of Presentation: ニューウェルシティー湯河原
  • Int'l Joint Research / Invited
• [Presentation] 『免疫分子遺伝学からがん制圧への道』AID/APOBECファミリーとその抗ウイルス活性 (2016)
  • Author(s): 村松正道
  • Organizer: 第32回(2016) 11月12日 京都賞記念ワークショップ 基礎科学部門
  • Place of Presentation: 京都大学 百周年時計台記念館
  • Int'l Joint Research / Invited
• [Presentation] Activation-induced cytidine deaminase down-regulates hepatitis B virus RNA through the RNA exosome (2015)
  • Author(s): 村松 正道（オーガナイザー 竹内 理（京都大学） / 久場 敬司（秋田大学））口頭発表
  • Organizer: BMB2015
  • Place of Presentation: 神戸商工会議所3F 神商ホールB
  • Year and Date: 2015-12-04
  • Invited
• [Presentation] Epsilon RNA is required for AID-mediated reduction of HBV transcripts. (2015)
  • Author(s): Que Lusheng Wakae Kousyo Kitamura Koichi Muramatsu Masamichi
  • Organizer: BMB2015
  • Place of Presentation: 神戸国際展示場3号館1階
  • Year and Date: 2015-12-01
• [Presentation] Epsilon RNA plays an important role in AID-dependent down-regulation of HBV transcripts. (2015)
  • Author(s): Liu Guangyan Wakae Kousyo Kitamura Koichi Muramatsu Masamichi
  • 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: 2015-11-24
• [Presentation] APOBEC3Hの多型とB型肝炎ウイルス複製阻害活性の検討 (2015)
  • Author(s): 坂本 直也 Wakae Kousyo Kitamura Koichi Muramatsu Masamichi
  • 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: 2015-11-24
• [Presentation] APOBECs: antiviral or oncogenic ? （口頭発表） (2015)
  • Author(s): 村松 正道
  • Organizer: Dalian Cancer Symposium： from basic research to clinical application
  • Place of Presentation: 大連大学（大連市、中国）
  • Year and Date: 2015-09-23
  • Int'l Joint Research / Invited
• [Presentation] 『APOBECとウイルス感染』 (2015)
  • Author(s): 村松正道
  • Organizer: ウイルス研セミナー「ウイルス研究の潮流」（共同利用・共同研究拠点事業）
  • Place of Presentation: 京都大学ウイルス研究所本館１階セミナー
  • Year and Date: 2015-09-02
  • Invited
• [Presentation] 『Next Generation Sequencing detects APOBEC3 mediated Hypermutation in Human Papillomavirus Type 16 Genome in vivo』 (2015)
  • Author(s): Kosho Wakae (1), Mitsuhiro Nakamura (2), Satoru Kondo (3), Hiroshi Fujiwara , Tomokazu Yoshizaki , Iwao Kukimoto , Tomoaki Nishiyama, and Masamichi Muramatsu : 口頭発表
  • Organizer: 2015 DNA tumor virus Meeting,International Centre for Genetic Engineering and Biotechnology（ICGEB）, An IUBMB symposium
  • Place of Presentation: イタリア Congress Centre of the Stazione Marittima
  • Year and Date: 2015-07-24
  • Int'l Joint Research
• [Presentation] パピローマウイルス16型感染におけるAPOBEC3タンパクの役割 （口頭発表） (2015)
  • Author(s): 村松正道
  • Organizer: 北陸腸内細菌研究会 総会・研究発表会
  • Place of Presentation: 富山第一ホテル（富山市）
  • Year and Date: 2015-07-11
• [Presentation] AIDによるRNA exosomeを介したHBV RNA分解 (2015)
  • Author(s): 喜多村晃一, Guoxin Liang, Guangyan Liu, 村松正道
  • Organizer: 日本生化学会北陸支部 第33回大会
  • Place of Presentation: 富山大学杉谷キャンパス
  • Year and Date: 2015-05-23
• [Presentation] Role of APOBEC3 in HPV expressing cell (2015)
  • Author(s): Ahasan Monjurul, Kosho Wakae and Masamichi Muramatsu
  • Organizer: Japan Cancer Society Symposium
  • Place of Presentation: ANA CROWN Plaza （石川・金沢）
  • Year and Date: 2015-01-21 – 2015-01-22
• [Presentation] AID-dependent down-regulation of HBV transcripts (2015)
  • Author(s): Guangyan Liu,Guoxin Liang, Kouichi Kitamura, Zhe Wang, Sajeda Chowdhury, Miki Koura, Kosho Wakae and Masamichi Muramatsu
  • Organizer: 日本癌学会シンポジウム
  • Place of Presentation: ANA CROWN Plaza （石川・金沢）
  • Year and Date: 2015-01-21 – 2015-01-22
• [Presentation] Activation-induced cytidine deaminase downregulates hepatitis B viral RNA through recruitment of the RNA exosome” (2014)
  • Author(s): 村松 正道
  • Organizer: 第43回日本免疫学会
  • Place of Presentation: 京都国際会議場(京都・京都）
  • Year and Date: 2014-12-11
• [Presentation] APOBEC3 suppresses infectivity of HPV pseudovirion (2014)
  • Author(s): Ahasan Monjurul, Kosho Wakae and Masamichi Muramatsu
  • Organizer: The 43rd Annual Meeting of The Japanese Society for Immunology
  • Place of Presentation: 京都国際会議場(京都・京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Role of host DNA repair factor in the maintenance of hepatitis B virus cccDNA (2014)
  • Author(s): 喜多村 晃一、島津 美幸、小浦 美樹、村松 正道
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 横浜パシフィコ(神奈川・横浜）
  • Year and Date: 2014-11-25
• [Presentation] AID inhibits multiple steps of the HBV replication (2014)
  • Author(s): 村松 正道
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜パシフィコ(神奈川・横浜）
  • Year and Date: 2014-11-12
• [Presentation] B型肝炎ウイルスcccDNAに対するAPOBECタンパク質の作用 (2014)
  • Author(s): 喜多村 晃一、島津 美幸、小浦 美樹、村松 正道
  • Organizer: 第62回日本ウイルス 学会学術集会
  • Place of Presentation: 横浜パシフィコ(神奈川・横浜）
  • Year and Date: 2014-11-12
• [Presentation] APOBEC3はHPV16 Pseudovirionの感染性を低下させる (2014)
  • Author(s): 若江亨祥、Ahasan Monjurul、王哲、喜多村晃一、森清一郎、柊元巌、中村充弘、藤原浩、村松正道
  • Organizer: 第６２回日本ウイルス学会学術集会
  • Place of Presentation: 横浜パシフィコ(神奈川・横浜）
  • Year and Date: 2014-11-12
• [Presentation] A novel antiviral function of activation-induced cytidine deaminase downregulates hepatitis B viral RNA through recruitment of the RNA exosome complex (2014)
  • Author(s): Guangyan Liu, Guoxin Liang, Kouichi Kitamura, Zhe Wang, Sajeda Chowdhury, Miki Koura, Kosho Wakae and Masamichi Muramatsu
  • Organizer: 第87回 日本生化学会大会
  • Place of Presentation: 京都国際会議場(京都・京都）
  • Year and Date: 2014-10-17 – 2014-10-18
• [Presentation] B型肝炎ウイルスゲノム上におけるウラシル化酵素APOBECとウラシル除去酵素UNGの役割 (2014)
  • Author(s): 村松 正道
  • Organizer: 日本遺伝学会第86回大会
  • Place of Presentation: 長浜バイオ大学（滋賀・長浜）
  • Year and Date: 2014-09-17
  • Invited
• [Presentation] APOBECデアミナーゼの新規抗ウイルス活性 (2014)
  • Author(s): 村松 正道
  • Organizer: 北陸腸内細菌研究会 総会・研究発表会
  • Place of Presentation: ホテル日航金沢（石川・金沢）
  • Year and Date: 2014-07-19
• [Remarks] 分子遺伝学教室
  • URL: http://molgenet.w3.kanazawa-u.ac.jp/index.html
• [Remarks] 金沢大学 医学系 分子遺伝学教室
  • URL: http://molgenet.w3.kanazawa-u.ac.jp/
• [Remarks] 研究室ホームページ
  • URL: http://molgenet.w3.kanazawa-u.ac.jp/
• [Remarks] 所属研究機関のホームページ中に配置されている研究室の紹介
  • URL: http://www.m.kanazawa-u.ac.jp/outline/gaiyou/dep01/dep1-04.html