Role of Pin1 in the proliferation of SARS-CoV-2

• Project/Area Number: 21K19380
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Hiroshima University
• Principal Investigator: ASANO TOMOICHIRO 広島大学, 医系科学研究科(医), 教授 (70242063)
• Co-Investigator(Kenkyū-buntansha): 中津 祐介 広島大学, 医系科学研究科(医), 准教授 (20452584) ; 山本屋 武 広島大学, 医系科学研究科(医), 助教 (50760013)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2022: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: Pin1 / SARS-CoV-2 / COVID-19 / ウイルス / コロナウイルス

Outline of Research at the Start

我々は、Pin1がSARS-CoV-2の増殖に必須の役割を果たしていることを発見した。具体的には、Vero/TMPRSS2細胞にPin1 siRNA処理あるいはPin1阻害剤添加を行うと、SARS-CoV-2の増殖がほぼ完全に抑制され、Vero/TMPRSS2細胞も障害されない結果を得た。そこで、SARS-CoV-2の増殖に関わるPin1の標的タンパクを同定し、増殖を誘導するメカニズムを解明する。さらに、Pin1あるいは、その標的タンパクをターゲットとするCOVID-19に対する新規治療へ進めるためのエビデンスを得る。

Outline of Final Research Achievements

Pin1 is involved in the pathogenesis of many diseases including cancers and metabolic syndrome. Furthermore, Pin1 is required to grow human immunodeficiency virus, hepatitis B virus, and other viruses. In this project, it was demonstrated that applying Pin1 knockdown or Pin1 inhibitors inhibited SARS-CoV-2 growth. Indeed, Pin1 was reported to bind to phosphorylated Ser79 in the Ser79-Pro sequence of the N protein. In addition, viral transcription of SARS-CoV-2 is inhibited by the use of Pin1 inhibitors, suggesting RNA synthesis of SARS-CoV-2 to likely be promoted by Pin1. The N protein has a sequence that is highly conserved among coronaviruses, but this Ser79-Pro sequence is not found in closely related viruses such as SARS-CoV and MERS-CoV and is specific to SARS-CoV-2. The Ser-Pro site of this N protein might be one of the causes of SARS-CoV2 exacerbation and spread of the infection.

Academic Significance and Societal Importance of the Research Achievements

新型コロナウイルスSARS-CoV-2によるパンデミックが起こり、多くの方が亡くなるなど多大な損失が生じ、私たちの生活も大きく変わってしまった。この感染症COVID-19を制御するための抗ウイルス剤は、まだ種類が限られており、新たな薬剤の開発が急務である。我々は、Pin1 siRNAによるPin1の阻害、あるいはPin1阻害薬の添加によって、培養細胞でのSARS-CoV-2の増殖を阻害することを見出した。我々が研究開発したPin1阻害薬は、他のCOVID-19治療薬とは異なる作用点をもつ薬剤であり、このようにPin1阻害薬をCOVID-19に対して使用することは新規の試みである。

Research Products

• [Journal Article] miR-582-5p targets Skp1 and regulates NF-κB signaling-mediated inflammation (2023)
  • Author(s): Li Rongzhi、Sano Tomomi、Mizokami Akiko、Fukuda Takao、Shinjo Takanori、Iwashita Misaki、Yamashita Akiko、Sanui Terukazu、Nakatsu Yusuke、Sotomaru Yusuke、Asano Tomoichiro、Kanematsu Takashi、Nishimura Fusanori
  • Journal Title: Archives of Biochemistry and Biophysics Volume: 734 Pages: 109501-109501
  • DOI: 10.1016/j.abb.2022.109501
  • Peer Reviewed / Open Access
• [Journal Article] The expression of prolyl isomerase Pin1 is expanded in the skin of patients with atopic dermatitis and facilitates IL‐33 expression in HaCaT cells (2022)
  • Author(s): Kanamoto Mayu、Takahagi Shunsuke、Aoyama Shunya、Kido Yuri、Nakanishi Mikako、Naito Miki、Kanna Machi、Yamamotoya Takeshi、Tanaka Akio、Hide Michihiro、Asano Tomoichiro、Nakatsu Yusuke
  • Journal Title: The Journal of Dermatology Volume: 50 Issue: 4 Pages: 462-471
  • DOI: 10.1111/1346-8138.16633
  • Peer Reviewed / Open Access
• [Journal Article] Par14 interacts with the androgen receptor, augmenting both its transcriptional activity and prostate cancer proliferation (2022)
  • Author(s): Naito M, Ikeda K, Aoyama S, Kanamoto M, Akasaka Y, Kido Y, Nakanishi M, Kanna M, Yamamotoya T, Matsubara A, Hinata N, Asano T, Nakatsu Y.
  • Journal Title: Cancer Med. Volume: - Issue: 7 Pages: 8464-8475
  • DOI: 10.1002/cam4.5587
  • Peer Reviewed / Open Access
• [Journal Article] Roles of peptidyl prolyl isomerase Pin1 in viral propagation (2022)
  • Author(s): Kanna M, Nakatsu Y, Yamamotoya T, Encinas J, Ito H, Okabe T, Asano T, Sakaguchi T.
  • Journal Title: Front Cell Dev Biol. Volume: 10 Pages: 1005325-1005325
  • DOI: 10.3389/fcell.2022.1005325
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] XAF1 overexpression exacerbates diabetes by promoting pancreatic β-cell apoptosis. (2022)
  • Author(s): Nishimura Y, Iwashita M, Hayashi M, Shinjo T, Watanabe Y, Zeze T, Yamashita A, Fukuda T, Sanui T, Sano T, Asano T, Nishimura F.
  • Journal Title: Acta Diabetol Volume: 59 Issue: 10 Pages: 1275-1286
  • DOI: 10.1007/s00592-022-01930-y
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of neuronal and muscular Trk-fused gene (TFG) defects in the development of neurodegenerative diseases (2022)
  • Author(s): Yamamotoya Takeshi、Hasei Shun、Akasaka Yasuyuki、Ohata Yukino、Nakatsu Yusuke、Kanna Machi、Fujishiro Midori、Sakoda Hideyuki、Ono Hiraku、Kushiyama Akifumi、Misawa Hidemi、Asano Tomoichiro
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 1966-1966
  • DOI: 10.1038/s41598-022-05884-7
  • Peer Reviewed / Open Access
• [Journal Article] Prolyl isomerase Pin1 plays an essential role in SARS-CoV-2 proliferation, indicating its possibility as a novel therapeutic target (2021)
  • Author(s): Yamamotoya T, Nakatsu Y, Kanna M, Hasei S, Ohata Y, Encinas J, Ito H, Okabe T, Asano T, Sakaguchi T.
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 18581-18581
  • DOI: 10.1038/s41598-021-97972-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 肝細胞のプロリン異性化酵素Pin1を介したNASH・肥満発症機構の解明 (2022)
  • Author(s): 中津 祐介、城戸 裕吏、青山 峻也、國吉 遼大、眞庭 理那、中西 魅加子、 浅野 知一郎
  • Organizer: 日本糖尿病学会
• [Presentation] プロリン異性化酵素Pin1による肝星細胞活性化と肝線維化への機序解明 (2022)
  • Author(s): 青山 俊也、中津 祐介、城戸 裕吏、中西 魅加子、浅野 知一郎
  • Organizer: 日本糖尿病学会
• [Presentation] プロリン異性化酵素Par14は、アンドロゲン受容体転写活性を亢進し、前立腺癌細胞の増殖を促進する。 (2022)
  • Author(s): 中津 祐介、内藤 美季、青山 峻也、金本 麻裕、城戸 裕吏、赤坂 保行、 浅野 知一郎
  • Organizer: 日本生化学会