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Okazaki Tomohiko

Institute for Genetic MedicineAssociate Professor

Researcher basic information

■ Degree
  • 博士 (工学), 東京大学, Mar. 2013
■ URL
researchmap URLホームページURL■ Various IDs
Researcher number
  • 50724598
J-Global ID■ Educational Organization

Career

■ Career
Career
  • Mar. 2021 - Present
    北海道大学, 遺伝子病制御研究所分子細胞生物研究室, 准教授
  • Apr. 2015 - Feb. 2021
    The University of Tokyo, 大学院薬学系研究科, 助教
  • Oct. 2013 - Mar. 2015
    The University of Tokyo, Graduate School of Pharmaceutical Sciences, 特任助教
  • May 2013 - Sep. 2013
    The University of Tokyo, Institute of Molecular and Cellular Biosciences Laboratory of Cell Signaling, 特任助教
  • Apr. 2013 - May 2013
    The University of Tokyo, Institute of Molecular and Cellular Biosciences Laboratory of Cell Signaling, 特任研究員
  • Mar. 2013
    東京大学大学院工学系研究科化学生命工学専攻修了博士号取得
  • Mar. 2006
    東京大学工学部卒業

Research activity information

■ Papers
  • MAVS phosphorylation acts as a cellular stress sensor that modulates antiviral immunity.
    Dongyi Zhao; Nao Morimoto; Riho Saito; Juri Yamada; Shuntaro Abe; Hidetaka Kosako; Yukiko Gotoh; Tomohiko Okazaki
    iScience, 28, 9, 113256, 113256, 19 Sep. 2025, [International Magazine]
    English, Scientific journal, Upon viral infection, cytosolic RIG-I-like receptors recognize viral RNA and activate innate immune responses through the mitochondrial antiviral-signaling protein (MAVS), leading to type I interferon (IFN) production and apoptosis. Cellular stress influences immune activation, but its impact on MAVS signaling remains largely unclear. Here, we show that MAVS undergoes phosphorylation via p38 MAPK signaling, activated by the stress-activated MAPKKK ASK1. This modification enhances MAVS interaction with TRAF, a key downstream adaptor, thereby promoting type I IFN induction. Oxidative and endoplasmic reticulum stress significantly amplified type I IFN expression upon viral infection, but this effect was attenuated in cells expressing MAVS mutants lacking phosphorylation sites. These findings suggest MAVS phosphorylation as a key mechanism integrating cellular stress signals into antiviral immunity. By linking the MAPK pathway to MAVS-dependent IFN expression, we propose MAVS phosphorylation as a cellular stress sensor that modulates antiviral immunity in a context-dependent manner.
  • Membrane topology inversion of GGCX mediates cytoplasmic carboxylation for antiviral defense.
    Tomohiko Okazaki; Keiji Nozaki; Nao Morimoto; Yuta Otobe; Riho Saito; Shuntaro Abe; Miyuki Okajima; Hikari Yoshitane; Tomohisa Hatta; Shun-Ichiro Iemura; Tohru Natsume; Hidetaka Kosako; Miwako Yamasaki; Satoshi Inoue; Takashi Kondo; Haruhiko Koseki; Yukiko Gotoh
    Science (New York, N.Y.), 389, 6755, 84, 91, 03 Jul. 2025, [International Magazine]
    English, Scientific journal, Mitochondrial antiviral signaling protein (MAVS) is an adaptor involved in antiviral immunity, but its regulation is not fully understood. We identified carboxylation of MAVS by vitamin K (VK)-dependent γ-glutamyl carboxylase (GGCX), which was unexpected owing to the reported membrane topology of GGCX. We found that GGCX could undergo topology inversion to carboxylate MAVS within the cytoplasm. This carboxylation enhanced the ability of MAVS to induce type I interferons while suppressing the induction of apoptosis. Genetic knockout of GGCX, a VK-free diet, or depletion of VK by inhibiting VK epoxide reductase 1 with warfarin increased viral susceptibility in mice. Thus, we identified a MAVS regulatory mechanism-the existence of cytoplasmic protein carboxylation and topological inversion of GGCX-and demonstrated how modulating VK levels may influence antiviral defense.
  • Control of mitochondrial dynamics and apoptotic pathways by peroxisomes.
    Chenxing Jiang; Tomohiko Okazaki
    Frontiers in cell and developmental biology, 10, 938177, 938177, 2022, [International Magazine]
    English, Scientific journal, Peroxisomes are organelles containing different enzymes that catalyze various metabolic pathways such as β-oxidation of very long-chain fatty acids and synthesis of plasmalogens. Peroxisome biogenesis is controlled by a family of proteins called peroxins, which are required for peroxisomal membrane formation, matrix protein transport, and division. Mutations of peroxins cause metabolic disorders called peroxisomal biogenesis disorders, among which Zellweger syndrome (ZS) is the most severe. Although patients with ZS exhibit severe pathology in multiple organs such as the liver, kidney, brain, muscle, and bone, the pathogenesis remains largely unknown. Recent findings indicate that peroxisomes regulate intrinsic apoptotic pathways and upstream fission-fusion processes, disruption of which causes multiple organ dysfunctions reminiscent of ZS. In this review, we summarize recent findings about peroxisome-mediated regulation of mitochondrial morphology and its possible relationship with the pathogenesis of ZS.
  • NUDT21 Links Mitochondrial IPS-1 to RLR-Containing Stress Granules and Activates Host Antiviral Defense.
    Saeko Aoyama-Ishiwatari; Tomohiko Okazaki; Shun-Ichiro Iemura; Tohru Natsume; Yasushi Okada; Yukiko Gotoh
    Journal of immunology (Baltimore, Md. : 1950), 206, 1, 154, 163, 01 Jan. 2021, [International Magazine]
    English, Scientific journal, Viral RNA in the cytoplasm of mammalian host cells is recognized by retinoic acid-inducible protein-I-like receptors (RLRs), which localize to cytoplasmic stress granules (SGs). Activated RLRs associate with the mitochondrial adaptor protein IPS-1, which activates antiviral host defense mechanisms, including type I IFN induction. It has remained unclear, however, how RLRs in SGs and IPS-1 in the mitochondrial outer membrane associate physically and engage in information transfer. In this study, we show that NUDT21, an RNA-binding protein that regulates alternative transcript polyadenylation, physically associates with IPS-1 and mediates its localization to SGs in response to transfection with polyinosinic-polycytidylic acid [poly(I:C)], a mimic of viral dsRNA. We found that despite its well-established function in the nucleus, a fraction of NUDT21 localizes to mitochondria in resting cells and becomes localized to SGs in response to poly(I:C) transfection. NUDT21 was also found to be required for efficient type I IFN induction in response to viral infection in both human HeLa cells and mouse macrophage cell line RAW264.7 cells. Our results together indicate that NUDT21 links RLRs in SGs to mitochondrial IPS-1 and thereby activates host defense responses to viral infection.
  • Peroxisomes control mitochondrial dynamics and the mitochondrion-dependent apoptosis pathway.
    Hideaki Tanaka; Tomohiko Okazaki; Saeko Aoyama; Mutsumi Yokota; Masato Koike; Yasushi Okada; Yukio Fujiki; Yukiko Gotoh
    Journal of cell science, 132, 11, 31 May 2019, [International Magazine]
    English, Scientific journal, Peroxisomes cooperate with mitochondria in the performance of cellular metabolic functions, such as fatty acid oxidation and the maintenance of redox homeostasis. However, whether peroxisomes also regulate mitochondrial fission-fusion dynamics or mitochondrion-dependent apoptosis remained unclear. We now show that genetic ablation of the peroxins Pex3 or Pex5, which are essential for peroxisome biogenesis, results in mitochondrial fragmentation in mouse embryonic fibroblasts (MEFs) in a manner dependent on Drp1 (also known as DNM1L). Conversely, treatment with 4-PBA, which results in peroxisome proliferation, resulted in mitochondrial elongation in wild-type MEFs, but not in Pex3-knockout MEFs. We further found that peroxisome deficiency increased the levels of cytosolic cytochrome c and caspase activity under basal conditions without inducing apoptosis. It also greatly enhanced etoposide-induced caspase activation and apoptosis, which is indicative of an enhanced cellular sensitivity to death signals. Taken together, our data unveil a previously unrecognized role for peroxisomes in the regulation of mitochondrial dynamics and mitochondrion-dependent apoptosis. Effects of peroxin gene mutations on mitochondrion-dependent apoptosis may contribute to pathogenesis of peroxisome biogenesis disorders.This article has an associated First Person interview with the first author of the paper.
  • An Unexpected Calm: Mfge8 Controls Stem Cell Quiescence and Maintenance.
    Tomohiko Okazaki; Yukiko Gotoh
    Cell stem cell, 23, 3, 311, 312, 06 Sep. 2018, [International Magazine]
    English, Scientific journal, Radial glia-like neural stem cells (RGLs) in the mouse hippocampus generate neurons throughout life, but RGL maintenance mechanisms remain unclear. In this issue of Cell Stem Cell, Zhou et al. (2018) identified Mfge8, a well-known mediator of the "eat-me" signal, as a factor that reinforces quiescence and protects the RGL niche from depletion.
  • ASK family in infection and inflammatory disease.
    Tomohiko Okazaki
    Advances in biological regulation, 66, 37, 45, Dec. 2017, [International Magazine]
    English, Scientific journal, Living organisms are continuously exposed to pathogens such as viruses and bacteria. Soon after a limited number of germline-encoded receptors, called pathogen recognition receptors, sense pathogen-associated molecular patterns, hosts trigger innate immune responses, including production of type Ⅰ interferons, proinflammatory cytokines, and cellular apoptosis, to limit propagation of invading pathogens. Importantly, these host responses are also activated during inflammatory diseases, irrespective of pathogen infection, and often play a causal role in pathogenesis and progression of these diseases, thereby implying an intimate link between immune responses and inflammatory disease. The apoptosis signal-regulating kinase (ASK) family belongs to the larger MAP3K family that controls various stress responses. Here, I summarize the critical roles of members of the ASK family during infection and inflammatory disease, and discuss the relationship between these two noxious conditions.
  • The ASK family kinases differentially mediate induction of type I interferon and apoptosis during the antiviral response (vol 10, pg 481, 2017)
    T. Okazaki; M. Higuchi; K. Takeda; K. Iwatsuki-Horimoto; M. Kiso; M. Miyagishi; H. Yanai; A. Kato; M. Yoneyama; T. Fujita; T. Taniguchi; Y. Kawaoka; H. Ichijo; Y. Gotoh
    SCIENCE SIGNALING, 10, 481, May 2017, [Peer-reviewed]
    English
  • PDK1-Akt pathway regulates radial neuronal migration and microtubules in the developing mouse neocortex.
    Yasuhiro Itoh; Maiko Higuchi; Koji Oishi; Yusuke Kishi; Tomohiko Okazaki; Hiroshi Sakai; Takaki Miyata; Kazunori Nakajima; Yukiko Gotoh
    Proceedings of the National Academy of Sciences of the United States of America, 113, 21, E2955-64, 24 May 2016, [International Magazine]
    English, Scientific journal, Neurons migrate a long radial distance by a process known as locomotion in the developing mammalian neocortex. During locomotion, immature neurons undergo saltatory movement along radial glia fibers. The molecular mechanisms that regulate the speed of locomotion are largely unknown. We now show that the serine/threonine kinase Akt and its activator phosphoinositide-dependent protein kinase 1 (PDK1) regulate the speed of locomotion of mouse neocortical neurons through the cortical plate. Inactivation of the PDK1-Akt pathway impaired the coordinated movement of the nucleus and centrosome, a microtubule-dependent process, during neuronal migration. Moreover, the PDK1-Akt pathway was found to control microtubules, likely by regulating the binding of accessory proteins including the dynactin subunit p150(glued) Consistent with this notion, we found that PDK1 regulates the expression of cytoplasmic dynein intermediate chain and light intermediate chain at a posttranscriptional level in the developing neocortex. Our results thus reveal an essential role for the PDK1-Akt pathway in the regulation of a key step of neuronal migration.
  • ASK "to be, or not to be?".
    Tomohiko Okazaki
    Oncotarget, 6, 33, 34055, 6, 27 Oct. 2015, [International Magazine]
    English
  • The ASK family kinases differentially mediate induction of type I interferon and apoptosis during the antiviral response.
    Tomohiko Okazaki; Maiko Higuchi; Kohsuke Takeda; Kiyoko Iwatsuki-Horimoto; Maki Kiso; Makoto Miyagishi; Hideyuki Yanai; Atsushi Kato; Mitsutoshi Yoneyama; Takashi Fujita; Tadatsugu Taniguchi; Yoshihiro Kawaoka; Hidenori Ichijo; Yukiko Gotoh
    Science signaling, 8, 388, ra78, 04 Aug. 2015, [International Magazine]
    English, Scientific journal, Viral infection activates host defense mechanisms, including the production of type I interferon (IFN) and the apoptosis of infected cells. We investigated whether these two antiviral responses were differentially regulated in infected cells. We showed that the mitogen-activated protein kinase (MAPK) kinase kinase (MAPKKK) apoptosis signal-regulating kinase 1 (ASK1) was activated in cells by the synthetic double-stranded RNA analog polyinosinic:polycytidylic acid [poly(I:C)] and by RNA viruses, and that ASK1 played an essential role in both the induction of the gene encoding IFN-β (IFNB) and apoptotic cell death. In contrast, we found that the MAPKKK ASK2, a modulator of ASK1 signaling, was essential for ASK1-dependent apoptosis, but not for inducing IFNB expression. Furthermore, genetic deletion of either ASK1 or ASK2 in mice promoted the replication of influenza A virus in the lung. These results indicated that ASK1 and ASK2 are components of the antiviral defense mechanism and suggested that ASK2 acts as a key modulator that promotes apoptosis rather than the type I IFN response. Because ASK2 is selectively present in epithelium-rich tissues, such as the lung, ASK2-dependent apoptosis may contribute to an antiviral defense in tissues with a rapid repair rate in which cells could be readily replaced.
  • Mitochondrial localization of the antiviral signaling adaptor IPS-1 is important for its induction of caspase activation.
    Tomohiko Okazaki; Maiko Higuchi; Yukiko Gotoh
    Genes to cells : devoted to molecular & cellular mechanisms, 18, 6, 493, 501, Jun. 2013, [International Magazine]
    English, Scientific journal, The RIG-I-like receptor (RLR) family of intracellular receptors detects viral nucleic acids and transmits an antiviral signal through the adaptor IPS-1. IPS-1 activation triggers host defense mechanisms, including rapid production of type I interferon (IFN), such as IFN-β, and induction of apoptosis. IPS-1 is mainly localized to mitochondria, and this localization has been proposed to be essential for inducing production of type I IFN and IFN-stimulated genes (ISGs). However, the importance of this mitochondrial localization of IPS-1 in executing apoptosis has remained unclear. Here, using IPS-1 mutants that were directed to specific subcellular locations such as cytoplasm, plasma membrane and mitochondria, we found that IPS-1's localization to mitochondria is important to activate caspase, but not to signal for IFN-β gene induction. We also found that IPS-1 possesses a BH3-like motif, which is commonly found among members of the Bcl-2 family. Mutations within this motif promoted IPS-1-induced caspase activation, suggesting that this domain acts as an intrinsic inhibitor domain of apoptosis induction. These results establish that the mitochondrial location of IPS-1 is essential to its ability to induce apoptosis.
  • Akt1 promotes focal adhesion disassembly and cell motility through phosphorylation of FAK in growth factor-stimulated cells.
    Maiko Higuchi; Rina Kihara; Tomohiko Okazaki; Ichiro Aoki; Shiro Suetsugu; Yukiko Gotoh
    Journal of cell science, 126, Pt 3, 745, 55, 01 Feb. 2013, [International Magazine]
    English, Scientific journal, The crosstalk between spatial adhesion signals and temporal soluble signals is key in regulating cellular responses such as cell migration. Here we show that soluble growth factors enhance integrin signaling through Akt phosphorylation of FAK at Ser695 and Thr700. PDGF treatment or overexpression of active Akt1 in fibroblasts increased autophosphorylation of FAK at Tyr397, an essential event for integrin turnover and cell migration. Phosphorylation-defective mutants of FAK (S695A and T700A) underwent autophosphorylation at Tyr397 and promoted cell migration in response to the integrin ligand fibronectin, but importantly, not in response to PDGF. This study has unveiled a novel function of Akt as an 'ignition kinase' of FAK in growth factor signaling and may shed light on the mechanism by which growth factors regulate integrin signaling.
■ Other Activities and Achievements
■ Syllabus
  • 生命科学研究, 2024年, 修士課程, 生命科学院
  • 生命科学実習, 2024年, 修士課程, 生命科学院
  • 生命科学論文講読Ⅰ, 2024年, 修士課程, 生命科学院
  • 生命科学論文講読Ⅱ, 2024年, 修士課程, 生命科学院
■ Research Themes
  • ストレスシグナルを仲介する新たな翻訳後修飾機構の発見と応用
    科学研究費助成事業
    01 Apr. 2024 - 31 Mar. 2027
    岡崎 朋彦
    日本学術振興会, 基盤研究(B), 北海道大学, 24K02172
  • 抗ウイルス防御における細胞内カルボキシル化修飾の包括的理解
    2021 - 2027
    岡崎 朋彦
    インフルエンザやSARS-CoV-2ウイルスはパンデミックを起こし人類の存続を脅かす為、ウイルス感染防御機構の解明は喫緊の課題です。本研究提案では、申請者が世界で初めて発見した「細胞内タンパク質カルボキシル化」によるウイルス抑制機構の包括的理解を目指すとともに、新たな抗ウイルス防御戦略を提案します。
    科学技術振興機構, 戦略的な研究開発の推進/創発的研究支援事業, 20352896
  • ストレス応答戦略における膜トポロジー制御の包括的理解
    科学研究費助成事業
    28 Jun. 2024 - 31 Mar. 2026
    岡崎 朋彦
    日本学術振興会, 挑戦的研究(萌芽), 北海道大学, 24K22007
  • 翻訳後修飾を介した抗ウイルス応答の選別機構の解析
    科学研究費助成事業
    01 Apr. 2021 - 31 Mar. 2024
    岡崎 朋彦
    ウイルス感染に対して、細胞は主に２つの初期防御応答をする。ひとつはⅠ型IFNを発現して分泌し、自身とその周囲の細胞にウイルス増殖が阻害される抗ウイルス状態を確立するという応答、もうひとつは細胞死を起こしてウイルスの増殖・伝搬を阻害する、という応答である。この2つの応答は状況によって宿主のダメージを起こすため、状況に応じた使い分けが個体生存に必須である。これまでに申請者は、ASKファミリーキナーゼがウイルス感染に対するⅠ型IFN 産生と細胞死誘導応答の選別に関わることを報告した(Okazaki et al., Science Signaling, 2015)。つまり、ASK1 homodimerはIFN発現を、ASK1-ASK2 heterodimerは細胞死を誘導することを見出したのである。しかし、これらのキナーゼがいかにして抗ウイルス応答の選別に関わるかは不明であった。申請者はそこで抗ウイルス応答におけるASKのリン酸化基質を探索し、IPS-1が基質となることを見出した。IPS-1は、細胞内ウイルスRNAを認識する受容体(RIG-I, MDA5)の下流で誘導されるIFN及び細胞死に必須の役割を果たす分子である。本研究では、リン酸化によってIPS-1の機能がいかなる制御を受けるか調べた。
    日本学術振興会, 基盤研究(C), 北海道大学, 21K07064
  • Differential control of the interefon and apoptotic responses against viral infection
    Grants-in-Aid for Scientific Research
    01 Apr. 2018 - 31 Mar. 2021
    Okazaki Tomohiko
    We previously found a mechanism by which the host cells differentially utilized two different responses, type I interferon (IFN) production to limit viral replication and cell death to eliminate infected cells. However, it was not clear whether viral elimination could actually be achieved by the usage of two differential antiviral responses. In this study, we found that viral elimination is indeed achieved by the differential usage.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), 東京大学, 18K07168
  • Differential regulation of the antiviral responses
    Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    01 Apr. 2016 - 31 Mar. 2019
    Okazaki Tomohiko
    I previously reported that type 1 interferon (IFN) production and apoptosis were differentially regulated in response to viral infection. However, the underlying molecular mechanism was remained largely unclear. In this study, we found that post-translational modification of IPS-1 switched its response from caspase activation to IFN production after viral infection.
    Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), The University of Tokyo, 16K19149
  • ウイルス感染及び二本鎖RNAによるIFN-βの発現制御メカニズムの解析
    科学研究費助成事業 特別研究員奨励費
    2008 - 2010
    岡崎 朋彦
    IPS-1はIFN産生、そして細胞死の誘導といった多彩な機能を介して抗ウイルス応答に貢献するが、IPS-1の活性がどのように制御されているのかは不明である。本研究では、IPS-1の翻訳後修飾に注目し、LC-MS/MSを用いてIPS-1の新規翻訳後修飾:γ-カルボキシル化を見出した。そして、その翻訳後修飾がIPS-1の機能制御に関わる可能性について検討した。まず、γ-カルボキシル化サイトにアラニン変異を導入した変異体IPS-1 4Aの機能を検討した。IPS-1の過剰発現によってIFN-β産生に必要な転写因子:IRF-3やp38/JNKのリン酸化が上昇することが、我々や他の研究によって明らかになっている。しかしながら、変異体IPS-1 4Aの過剰発現はIRF-3やp38/JNKのリン酸化には全く影響がないが、カスパーゼの活性化を著しく亢進させることが分かった。次にカルボキシル化酵素GGCXのノックダウンを行った。すると、ノックダウンしたHeLa S3細胞においては、dsRNA刺激によるカスパーゼの活性化が亢進することがわかった。また、293T細胞において、IPS-1の過剰発現によるカスパーゼの活性化は、GGCXの共発現によって抑制されることもわかった。以上の結果より、GGCXによるγ-カルボキシル化を介した細胞死の抑制効果は、IPS-1のγ-カルボキシル化を介している可能性が強く示唆された。本研究により、抗ウイルス応答において重要な働きを担うIPS-1において、翻訳後修飾を介した機能の切り替えが行われている可能性が示唆された。IPS-1はウイルス感染によるIFNの産生と細胞死の両方を制御する必須の分子であることが知られていたが、その活性化制御はこれまでほとんど分かっていなかった。現在、産総研の夏目徹博士との共同研究により、IPS-1の機能の切り替えを担う因子の探索を行っている。
    日本学術振興会, 特別研究員奨励費, 東京大学, 08J06663