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Yoshinori Fukui Last modified date:2023.05.26

Graduate School
Administration Post
Director of the Medical Institute of Bioregulation

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Academic Degree
Doctor of Medical Science
Country of degree conferring institution (Overseas)
Field of Specialization
Immunogenetics, Molecular Immunology, Cell Biology
Total Priod of education and research career in the foreign country
Outline Activities
Remodeling of the actin cytoskeleton is a fundamental biological response that regulates various cellular functions in the immune system. The aim of my research is to elucidate the mechanism by which remodeling of the actin cytoskeleton is induced in lymphoid and myeloid cells downstream of various receptors, and to define its relevance to cellular functions. This accomplishment will lead to the development of new therapeutics for intractable diseases such as autoimmune diseases, graft rejection and infectious diseases.
Research Interests
  • Remodeling of the actin cytoskeleton in the immune system
    keyword : cytoskeleton, cell migration, antigen recognition, development of the immune system, G proteins
    2001.01Remodeling of the actin cytoskeleton is a fundamental biological response that regulates various cellular functions in the immune system. The aim of this study is to elucidate the mechanism by which remodeling of the actin cytoskeleton is induced in lymphoid and myeloid cells following the stimulation of various receptors, and to define its relevance to cellular functions. This accomplishment will lead to the development of new therapeutics for intractable diseases such as autoimmune diseases, graft rejection and infectious diseases..
Academic Activities
1. Toyoshi Yanagihara, Kentaro Hata, Kunihiro Suzuki, Keisuke Matsubara, Kazufumi Kunimura, Kazuya Tsubouchi, Daisuke Eto, Hiroyuki Ando, Maki Uehara, Satoshi Ikegame, Yoshinori Fukui, Isamu Okamoto, Expansion of ST2-expressing macrophages in a patient with bronchiolitis obliterans syndrome., ERJ Open Research, 10.1183/23120541.00033-2023, in press, 2023.03.
2. Kenji Morino, Kazufumi Kunimura, Yuki Sugiura, Yoshihiro Izumi, Keisuke Matsubara, Sayaka Akiyoshi, Rae Maeda, Kenichiro Hirotani, Daiji Sakata, Seiya Mizuno, Satoru Takahashi, Takeshi Bamba, Takehito Uruno, Yoshinori Fukui, Cholesterol sulfate limits neutrophil recruitment and gut inflammation during mucosal injury., Front. Immunol., 10.3389/fimmu.2023.1131146, 14:1131146, 2023.03.
3. Kazufumi Kunimura , Sayaka Akiyoshi, Takehito Uruno, Keisuke Matsubara, Daiji Sakata, Kenji Morino, Kenichiro Hirotani, Yoshinori Fukui, DOCK2 regulates MRGPRX2/B2-mediated mast cell degranulation and drug-induced anaphylaxis., J. Allergy Clin. Immunol., 10.1016/j.jaci.2023.01.029., 2023.02.
4. Ho Namkoong, (他473名) Yoshinori Fukui, (他14名) Yukinori Okada, DOCK2 is involved in the host genetics and biology of severe COVID-19, Nature, 609:754-760, 2022.08.
5. Kazufumi Kunimura, Kazuhiko Yamamura, Takeshi Nakahara, Makiko Kido-Nakahara, Takehito Uruno, Yoshinori Fukui, Identification of a functional DOCK8 gene polymorphism associated with atopic dermatitis, Allergy, in press, 2021.12.
6. Takaaki Tatsuguchi, Takehito Uruno, Yuki Sugiura, Daiji Sakata, Yoshihiro Izumi, Tetsuya Sakurai, Yuko Hattori, Eiji Oki, Naoto Kubota, Koshiro Nishimoto, Masafumi Oyama, Kazufumi Kunimura, Takuto Ohki, Takeshi Bamba, Hideaki Tahara, Michiie Sakamoto, Masafumi Nakamura, Makoto Suematsu, Yoshinori Fukui, Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells., Int. Immunol. , 34:277-289, 2022.04.
7. Takaaki Tatsuguchi, Takehito Uruno, Yuki Sugiura, Kounosuke Oisaki, Daisuke Takaya, Daiji Sakata, Yoshihiro Izumi, Takaya Togo, Yuko Hattori, Kazufumi Kunimura, Tetsuya Sakurai, Teruki Honma, Takeshi Bamba, Masafumi Nakamura, Motomu Kanai, Makoto Suematsu, Yoshinori Fukui, Pharmacological intervention of cholesterol sulfate-mediated T cell exclusion promotes antitumor immunity, Biochem. Biophys. Res. Commun., 609:183-188, 2022.06.
8. Kazufumi Kunimura, Yoshinori Fukui, The molecular basis for IL-31 production and IL-31-mediated itch transmission: from biology to drug development., Int. Immunol., 10.1093/intimm/dxab065, 33, 731-736, 2021.09.
9. Keisuke Matsubara, Kazufumi Kunimura, Nana Yamane, Ryosuke Aihara, Tetsuya Sakurai, Daiji Sakata, Takehito Uruno, Yoshinori Fukui, DOCK8 dificiency causes a skewing to type 2 immunity in the gut with expansion of group 2 innate lymphoid cells., Biochem. Biophys. Res. Commun., 10.1016/j.bbrc.2021.04.094, 559, 135-140, 2021.06.
10. Yasuhisa Kamikaseda, Takehito Uruno, Kazufumi Kunimura, Akihito Harada, Kuniko Saiki, Kounosuke Oisaki, Daiji Sakata, Takeshi Nakahara, Makiko Kido-Nakahara, Motomu Kanai, Seiji Nakamura, Yasuyuki Ohkawa, Masutaka Furue, Yoshinori Fukui, Target inhibition of EPAS1-driven IL-31 production by a small-molecule compound., J. Allergy Clin. Immun., 10.1016/j.jaci.2021.03.029, 148, 633-638, in press, 2021.04, Background: IL-31 is a major pruritogen associated with atopic dermatitis (AD). Although a specific antibody for IL-31 receptor has been shown to alleviate pruritus in patients with AD, therapeutic approaches to inhibit IL-31 production remain unexploited. IL-31 production by helper T cells critically depends on the transcription factor EPAS1, which mediates IL31 promoter activation in collaboration with SP1.
Objective: We aimed at developing small-molecule inhibitors that selectively block IL-31 production by helper T cells.
Methods: We generated the reporter cell line that inducibly expressed EPAS1 in the presence of doxycycline to mediate Il31 promoter activation, and screened 9,600 chemical compounds. The selected compounds were further examined using helper T cells from a spontaneous mouse model of AD and those from patients with AD.
Results: We have identified 4-(2-(4-isopropylbenzylidene)hydrazineyl)benzoic acid (IPHBA) as an inhibitor of IL-31 induction. Although IPHBA did not affect non-specific T cell proliferation, IPHBA inhibited antigen–induced IL-31 production by helper T cells from both an AD mouse model and AD patients, without affecting other cytokine productions and hypoxic responses. In line with this, itch responses induced by adoptive transfer of IL-31-producing helper T cells were attenuated when mice were orally treated with IPHBA. Mechanistically, IPHBA inhibited association between EPAS1 and SP1, resulting in defective recruitment of both transcription factors to the specific sites of IL31 promoter. We also determined the structure–activity relationship of IPHBA by synthesizing and analyzing 201 analog compounds.
Conclusion: IPHBA could be a potential drug lead to inhibit EPAS1-driven IL-31 production..
11. Tetsuya Sakurai, Mutsuko Kunimoto-Niino, Kazufumi Kunimura, Nana Yamane, Daiji Sakata, Ryosuke Aihara, Tomoharu Yasuda, Shigeyuki Yokoyama, Mikako Shirouzu, Yoshinori Fukui, Takehito Uruno, A conserved PI(4,5)P2-binding domain is critical for immune regulatory function of DOCK8., Life Sci. Alliance, 10.26508/lsa.202000873, 4, 4, e202000873, 2021.02.
12. Ryosuke Aihara, Kazufumi Kunimura, Mayuki Watanabe, Takehito Uruno, Nana Yamane, Tetsuya Sakurai, Daiji Sakata, Fusanori Nishimura, Yoshinori Fukui, DOCK8 controls survival of group 3 innate lymphoid cells in the gut through Cdc42 activation., Int. Immunol. , 10.1093/intimm/dxaa066, 33, 149-160, 2021.03.
13. Kazufumi Kunimura, Daiji Sakata, Xin Tun, Takehito Uruno, Miho Ushijima, Tomoya Katakai, Akira Shiraishi, Ryosuke Aihara, Yasuhisa Kamikaseda, Keisuke Matsubara, Hirokazu Kanegane, Shinichiro Sawa, Gerard Eberl, Shouichi Ohga, Yasunobu Yoshikai, Yoshinori Fukui, S100A4 Protein Is Essential for the Development of Mature Microfold Cells in Peyer's Patches, Cell Rep., 10.1016/j.celrep.2019.10.091, 26, 9, 2823-2834.e7, 2019.11.
14. Daiji Sakata, Takehito Uruno, Keisuke Matsubara, Tsugunobu Andoh, Kazuhiko Yamamura, Yuki Magoshi, Kazufumi Kunimura, Yasuhisa Kamikaseda, Masutaka Furue, Yoshinori Fukui, Selective role of neurokinin B in IL-31-induced itch response in mice, J. Allergy. Clin. Immunol., 10.1016/j.jaci.2019.06.031, 144, 4, 1130-1133.e8, 2019.10, Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by recurrent eczematous legions and intense itch. Itch can be induced by various chemical mediators. Among them, much attention has been paid to interleukin 31 (IL-31) as an AD-associated itch mediator since the discovery of the pruritogenic action of IL-31 in mice. IL-31 is mainly produced by CD4+ T cells and transmits the signals via a heterodimeric receptor composed of IL-31 receptor A (IL-31RA) and oncostatin M receptor (OSMR), both of which are expressed in dorsal root ganglion (DRG) neurons. However, the neuronal mechanism underlying IL-31–induced itch sensation is poorly understood. By analyzing a mouse model for atopic dermatitis, we found that the expression of Tac2, which encodes neurokinin B (NKB), markedly increased in the DRG neurons in response to IL-31. While NKB-deficient mice lost IL-31–induced itch response, scratching behaviors induced by other pruritogens such as histamine, chloroquine and protease-activated receptor 2 (PAR2) agonist were unaffected in the absence of NKB. NKB transmits the signal through neurokinin 3 receptor (NK3R), a G protein-coupled tachykinin receptor. When wild-type mice were pre-treated with NK3R antagonists, IL-31–induced scratching was significantly attenuated, without affecting itch responses induced by other pruritogens. These results indicate that NKB-NK3R axis could be a novel therapeutic target controlling IL-31–induced itch in AD patients..
15. Kazufumi Kunimura, Takehito Uruno, Yoshinori Fukui, DOCK-family proteins : key players in immune surveillance mechanisms, Int. Immunol., 10.1093/intimm/dxz067, 2019.10.
16. Tetsuya Sakurai, Takehito Uruno, Takaaki Tatsuguchi, Kazuhiko Yamamura, Miho Ushijima, Yuko Hattori, Mutsuko Kukimoto-Niino, Chiemi Mishima-Tsumagari, Mayuki Watanabe, Makoto Suematsu, Yoshinori Fukui, Cholesterol sulfate is a DOCK2 inhibitor that mediates tissue-specific immune evasion in the eye, Sci. Signal. , 10.1126/scisignal.aao4874, 11, 541, 2018.07, Although immune responses are essential to protect the body from infection, they can also harm tissues. Certain tissues and organs, including the eye, constitute specialized microenvironments that locally inhibit immune reactivity. Dedicator of cytokinesis protein 2 (DOCK2) is a Rac-specific guanine nucleotide exchange factor (GEF) that is predominantly found in hematopoietic cells. DOCK2 plays a key role in immune surveillance because it is essential for the activation and migration of leukocytes. DOCK2 mutations cause severe immunodeficiency in humans. We found that DOCK2-mediated Rac activation and leukocyte migration were effectively inhibited by cholesterol sulfate (CS), but not by cholesterol or other sulfated steroids. CS bound to the catalytic domain of DOCK2 and suppressed its GEF activity. Mass spectrometric quantification revealed that CS was most abundantly produced in the Harderian gland, which provides the lipids that form the oily layer of the tear film. Sulfation of cholesterol is mediated by the sulfotransferases SULT2B1b and, to a lesser extent, SULT2B1a, which are produced from the same gene through alternative splicing. By genetically inactivating Sult2b1, we showed that the lack of CS in mice augmented ultraviolet- and antigen-induced ocular surface inflammation, which was suppressed by administration of eye drops containing CS. Thus, CS is a naturally occurring DOCK2 inhibitor and contributes to the generation of the immunosuppressive microenvironment in the eye..
17. Masutaka Furue, K. Yamamura, Makiko Nakahara, Takeshi Nakahara, Yoshinori Fukui, Emerging role of interleukin-31 and interleukin-31 receptor in pruritus in atopic dermatitis, Allergy: European Journal of Allergy and Clinical Immunology, 10.1111/all.13239, 73, 1, 29-36, 2018.01, Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder associated with skin barrier dysfunction. The lesional skin of AD exhibits T helper 2 (TH2)-deviated immune reactions. Interleukin-31 (IL-31), preferentially produced from TH2 cells, is a potent pruritogenic cytokine, and its systemic and local administration induces scratching behavior in rodents, dogs and monkeys. Recent clinical trials have revealed that administration of an anti-IL-31 receptor antibody significantly alleviates pruritus in patients with AD. In this review, we summarize recent topics related to IL-31 and its receptor with special references to atopic itch..
18. Lauren A. Peters, Jacqueline Perrigoue, Arthur Mortha, Alina Iuga, Won Min Song, Eric M. Neiman, Sean R. Llewellyn, Antonio Di Narzo, Brian A. Kidd, Shannon E. Telesco, Yongzhong Zhao, Aleksandar Stojmirovic, Jocelyn Sendecki, Khader Shameer, Riccardo Miotto, Bojan Losic, Hardik Shah, Eunjee Lee, Minghui Wang, Jeremiah J. Faith, Andrew Kasarskis, Carrie Brodmerkel, Mark Curran, Anuk Das, Joshua R. Friedman, Yoshinori Fukui, Mary Beth Humphrey, Brian M. Iritani, Nicholas Sibinga, Teresa K. Tarrant, Carmen Argmann, Ke Hao, Panos Roussos, Jun Zhu, Bin Zhang, Radu Dobrin, Lloyd F. Mayer, Eric E. Schadt, A functional genomics predictive network model identifies regulators of inflammatory bowel disease, Nature Genetics, 10.1038/ng.3947, 49, 10, 1437-1449, 2017.10, A major challenge in inflammatory bowel disease (IBD) is the integration of diverse IBD data sets to construct predictive models of IBD. We present a predictive model of the immune component of IBD that informs causal relationships among loci previously linked to IBD through genome-wide association studies (GWAS) using functional and regulatory annotations that relate to the cells, tissues, and pathophysiology of IBD. Our model consists of individual networks constructed using molecular data generated from intestinal samples isolated from three populations of patients with IBD at different stages of disease. We performed key driver analysis to identify genes predicted to modulate network regulatory states associated with IBD, prioritizing and prospectively validating 12 of the top key drivers experimentally. This validated key driver set not only introduces new regulators of processes central to IBD but also provides the integrated circuits of genetic, molecular, and clinical traits that can be directly queried to interrogate and refine the regulatory framework defining IBD..
19. Toyoshi Yanagihara, Takahiro Tomino, Takehito Uruno, Yoshinori Fukui, Thymic epithelial cell–specific deletion of Jmjd6 reduces Aire protein expression and exacerbates disease development in a mouse model of autoimmune diabetes, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2017.05.113, 489, 1, 8-13, 2017.07, Thymic epithelial cells (TECs) establish spatially distinct microenvironments in which developing T cells are selected to mature or die. A unique property of medullary TECs is their expression of thousands of tissue-restricted self-antigens that is largely under the control of the transcriptional regulator Aire. We previously showed that Jmjd6, a lysyl hydroxylase for splicing regulatory proteins, is important for Aire protein expression and that transplantation of Jmjd6-deficient thymic stroma into athymic nude mice resulted in multiorgan autoimmunity. Here we report that TEC-specific deletion of Jmjd6 exacerbates development of autoimmune diabetes in a mouse model, which express both ovalbumin (OVA) under the control of the rat insulin gene promoter and OT-I T cell receptor specific for OVA peptide bound to major histocompatibility complex class I Kb molecules. We found that Aire protein expression in mTECs was reduced in the absence of Jmjd6, with retention of intron 2 in Aire transcripts. Our results thus demonstrate the importance of Jmjd6 in establishment of immunological tolerance in a more physiological setting..
20. Hirotada Tajiri, Takehito Uruno, Takahiro Shirai, Daisuke Takaya, Shigeki Matsunaga, Daiki Setoyama, Mayuki Watanabe, Mutsuko Kukimoto-Niino, Kounosuke Oisaki, Miho Ushijima, Fumiyuki Sanematsu, Teruki Honma, Takaho Terada, Eiji Oki, Senji Shirasawa, Yoshihiko Maehara, Dongchon Kang, Jean François Côté, Shigeyuki Yokoyama, Motomu Kanai, Yoshinori Fukui, Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1, Cell Reports, 10.1016/j.celrep.2017.04.016, 19, 5, 969-980, 2017.05, Oncogenic Ras plays a key role in cancer initiation but also contributes to malignant phenotypes by stimulating nutrient uptake and promoting invasive migration. Because these latter cellular responses require Rac-mediated remodeling of the actin cytoskeleton, we hypothesized that molecules involved in Rac activation may be valuable targets for cancer therapy. We report that genetic inactivation of the Rac-specific guanine nucleotide exchange factor DOCK1 ablates both macropinocytosis-dependent nutrient uptake and cellular invasion in Ras-transformed cells. By screening chemical libraries, we have identified 1-(2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-pyrrolidinylsulfonyl-2(1H)-pyridone (TBOPP) as a selective inhibitor of DOCK1. TBOPP dampened DOCK1-mediated invasion, macropinocytosis, and survival under the condition of glutamine deprivation without impairing the biological functions of the closely related DOCK2 and DOCK5 proteins. Furthermore, TBOPP treatment suppressed cancer metastasis and growth in vivo in mice. Our results demonstrate that selective pharmacological inhibition of DOCK1 could be a therapeutic approach to target cancer cell survival and invasion..
21. Akira Shiraishi, Takehito Uruno, Fumiyuki Sanematsu, Miho Ushijima, Daiji Sakata, Toshiro Hara, Yoshinori Fukui, DOCK8 protein regulates macrophage migration through Cdc42 protein activation and LRAP35a protein interaction, Journal of Biological Chemistry, 10.1074/jbc.M116.736306, 292, 6, 2191-2202, 2017.02, DOCK8 is an atypical guanine nucleotide exchange factor for Cdc42, and its mutations cause combined immunodeficiency in humans. Accumulating evidence indicates that DOCK8 regulates the migration and activation of various subsets of leukocytes, but its regulatory mechanism is poorly understood. We here report that DOCK8-deficient macrophages exhibit a migration defect in a 2D setting. Although DOCK8 deficiency in macrophages did not affect the global Cdc42 activation induced by chemokine stimulation, rescue experiments revealed that the guanine nucleotide exchange factor activity of DOCK8 was required for macrophage migration. We found that DOCK8 associated with LRAP35a, an adaptor molecule that binds to the Cdc42 effector myotonic dystrophy kinase-related Cdc42-binding kinase, and facilitated its activity to phosphorylate myosin II regulatory light chain. When this interaction was disrupted in WT macrophages, they showed a migration defect, as seen in DOCK8-deficient macrophages. These results suggest that, during macrophage migration, DOCK8 links Cdc42 activation to actomyosin dynamics through the association with LRAP35a..
22. Kazuhiko Yamamura, Takehito Uruno, Akira Shiraishi, Yoshihiko Tanaka, Miho Ushijima, Takeshi Nakahara, Mayuki Watanabe, Makiko Kido-Nakahara, Ikuya Tsuge, Masutaka Furue, Yoshinori Fukui, The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction, Nature communications, 10.1038/ncomms13946, 8, 2017.01, Mutations of DOCK8 in humans cause a combined immunodeficiency characterized by atopic dermatitis with high serum IgE levels. However, the molecular link between DOCK8 deficiency and atopic skin inflammation is unknown. Here we show that CD4+ T cells from DOCK8-deficient mice produce large amounts of IL-31, a major pruritogen associated with atopic dermatitis. IL-31 induction critically depends on the transcription factor EPAS1, and its conditional deletion in CD4+ T cells abrogates skin disease development in DOCK8-deficient mice. Although EPAS1 is known to form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) and control hypoxic responses, EPAS1-mediated Il31 promoter activation is independent of ARNT, but in collaboration with SP1. On the other hand, we find that DOCK8 is an adaptor and negative regulator of nuclear translocation of EPAS1. Thus, EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction in CD4+ T cells..
23. Toyoshi Yanagihara, Fumiyuki Sanematsu, Sato T, Takehito Uruno, DUAN XUEFENG, Takahiro Tomino, Yosuke Harada, Mayuki Watanabe, YUQING WANG, Yoshihiko Tanaka, Yoichi Nakanishi, M. Suyama, Yoshinori Fukui, Intronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus, Nature Commun., 6, 8820, 2015.11.
24. Guo X, Shi N, Cui X-B, Wang J-N, Yoshinori Fukui, Chen S-Y, Dedicator of cytokinesis 2, a novel regulator for smooth muscle phenotypic modulation and vascular remodeling, Cir. Res. , 116, e71-e80, 2015.05.
25. Abu-Thuraia A, Gauthier R, Chidiac R, Yoshinori Fukui, Screaton RA, Gratton JP, Cote JF, Axl phosphorylates Elmo scraffold proteins to promote Rac activation and cell invasion, Mol. Cell. Biol., 35, 76-87, 2015.01.
26. Watanabe M, Terasawa M, Miyano K, Yanagihara T, 宇留野 武人, Fumiyuki Sanematsu, Cote JF, Hideki Sumimoto, Yoshinori Fukui, DOCK2 and DOCK5 act additively in neutrophils to regulate chemotaxis, superoxide production, and extracellular trap formation, J. Immunol., 193, 5660-5667, 2014.12.
27. Sreeramkumar V, Adrover JM, Ballesteros I, Cuartero MI, Rossaint J, Bilbao I, Nacher M, Pitaval C, Radovanovic I, Yoshinori Fukui, McEver RP, Filippi M-D, Lizasoain I, Ruiz-Cabello J, Zarbock A, Moro MA, Hidalgo A, Neutrophils scan for activated platelets to initiate inflammation, Science, 346, 1234-1238, 2014.12.
28. Moalli F, Cupovic J, Thelen F, Halbherr P, Yoshinori Fukui, Narumiya S, Ludewig B, Stein JV, Thromboxane A2 acts as tonic immunoregulator by preferential disruption of low-avidity CD4+ T cell-dendritic cell interactions, J. Exp. Med., 211, 2507-2517, 2014.12.
29. Wen Y, Elliott MJ, Huang Y, Miller TO, Corbin DR, Hussain L-R, Ratajczak MZ, Yoshinori Fukui, Ilsars ST, DOCK2 is critical for CD8+TCR- graft facilitating cells to enhance engraftment of hematopoietic stem and progenitor cells, Stem Cells, 32, 2732-2734, 2014.10.
30. Kana Ogawa, Yoshihiko Tanaka, Takehito Uruno, DUAN XUEFENG, Yosuke Harada, Fumiyuki Sanematsu, Kazuhiko Yamamura, 寺澤 公男, Akihiko Nishikimi, JF Côté, Yoshinori Fukui, DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation, J. Exp.Med., 211, 1407-1419, 2014.07, マスト細胞は、細胞内に分泌顆粒を有しており、これに含まれるケミカルメディエーターを細胞外部に放出することで、アナフィラキシーと呼ばれる重篤なアレルギー反応を惹起する。マスト細胞はその表面にIgE抗体の高親和性受容体であるFcεRIを発現しており、これが抗原およびIgE抗体で架橋されると微小管のダイナミックな再構築が誘導され、脱顆粒反応がおこる。しかしながらこれまで、FcεRI近位のシグナル伝達機構に関してよく解析されているものの、微小管動態を制御する遠位のシグナル経路については依然として不明な点が多い。本研究において私達は、Racのグアニンヌクレオチド交換因子 (GEF)であるDOCK5が、マスト細胞の脱顆粒反応を重要な役割を演じていることを示す。私達は、DOCK5欠損マウスが全身性および皮膚アナフィラキシーショックに抵抗性を示すことを見いだした。驚いたことに、DOCK5が持つRac GEFとしての活性は、マスト細胞の脱顆粒反応に必要ではなかった。代わり、DOCK5はNck2やAktと会合し、GSK3βのリン酸化と不活性化を制御することで、微小管動態をコントロールしており、これらの分子との会合をブロックすると、微小管形成や脱顆粒反応が著しく障害された。以上より、DOCK5はアダプターとして機能し、マスト細胞の脱顆粒反応に重要な微小管動態を制御していることを明らかにした。.
31. Damoulakis G, Gambardella L, Rossman K, Lawson C, Anderson K, Yoshinori Fukui, Welch H, Der C, Stephens L, Hawkins P, P-Rex1 directly activates RhoG to regulate GPCR-driven Rac signalling and actin polarity in neutrophils., J. Cell Sci., 127, 2589-2600, 2014.06.
32. Laurin M, Dumouchel A, Yoshinori Fukui, Côté JF, The Rac-specific exchange factors Dock1 and Dock5 are dispensable for the establishment of the glomerular filtration barrier in vivo., Small GTPases , 4, 4, 2013.12.
33. Le Floc’h A, Yoshihiko Tanaka, Bantilan BS, Voisinne G, Altan-Bonnet G, Yoshinori Fukui, Huse M, Annular PIP3 accumulation controls actin architecture and modulates cytotoxicity at the immunological synapse. , J. Exp. Med., 210, 2721-2737, 2013.11.
34. Akihiko Nishikimi, M Kukimoto-Niino, S Yokoyama, Yoshinori Fukui, Immune regulatory functions DOCK family proteins in health and disease., Exp.Cell.Res., 319, 15, 2343-2349, 2013.09.
35. Sachiko Kamakura, Masatoshi Nomura, Jyunya Hayase, Y Iwakiri, Akihiko Nishikimi, Ryoichi Takayanagi, Yoshinori Fukui, Hideki Sumimoto, The cell polarity protein mlnsc regulates neutrophil chemotaxis via a noncanonical G protein signaling pathway., Dev. Cell., 26, 3, 292-302, 2013.08.
36. Yusuke Sakai, Yoshihiko Tanaka, Tohoshi Yanagihara, Mayuki Watanabe, DUAN XUEFENG, 寺澤 公男, Akihiko Nishikimi, Fumiyuki Sanematsu, Yoshinori Fukui, The Rac activator DOCK2 regulates natural killer cell-mediated cytotoxicity in mice through the lytic synapse formation., Blood, 122, 3, 386-393, 2013.05.
37. M Laurin, J Huber, A Pelletier, T Houalla, M Park, Yoshinori Fukui, B Haibe-Kains, WJ Muller, JF Côté, Rac-specific guanine nucleotide exchange factor DOCK1 is a critical regulator of HER2-mediated breast cancer metastasis., Proc.Natl.Acad.Sci.USA, 110, 18, 7434-7439, 2013.03.
38. Cimino PJ, Yang Y, Li X, Hemingway JF, Cherne MK, Khademi SB, Fukui Y, Montine KS, Montine TJ, Keene CD, Ablation of the microglial protein DOCK2 reduces amyloid burden in a mouse model of alzheimer's disease, Exp. Mol. Pathol., 10.1016/j.yexmp.2013.01.002., in press, 1-5, 2013.01.
39. Unoki M, Masuda A, Dohmae N, Arita K, Yoshimatsu M, Iwai Y, Fukui Y, Ueda K, Hamamoto R, Shirakawa M, Sasaki H, Nakamura Y, Lysyl 5-Hydroxylation, a novel histone modification, by jumonji domain containing 6(JMJD6), J. Biol. Chem., in press, 1-5, 2013.01.
40. Fumiyuki Sanematsu, Akihiko Nishikimi, Mayuki Watanabe, T Hongu, Yoshihiko Tanaka, Y Kanaho, JF Côté, Yoshinori Fukui, Phosphatidic acid-dependent recruitment and function of the Rat activator DOCK1 during dorsal ruffle formation, J. Biol. Chem., 288, 8092-8100, 2013.01.
41. Shigeo Fujimori, Naoya Hirai, Hiroyuki Ohashi, Kazuyo Masuoka, Akihiko Nishikimi, Yoshinori Fukui, Takanori Washio, Tomohiro Oshikubo, Tatsuhiro Yamashita, Etsuko Miyamoto-Sato, Next-generation sequencing coupled with a cell-free display technology for high-throughput production of reliable interactome data, Scientific Reports, 10.1038/srep00691, 2:691, 1-5, 2012.10.
42. Masao Terasawa, Takehito Uruno, Sayako Mori, Mutsuko Kukimoto-Niino, Akihiko Nishikimi, Fumiyuki Sanematsu, Yoshihiko Tanaka, Shigeyuki Yokoyama, Yoshinori Fukui, Dimerization of DOCK2 is essential for DOCK2-mediated Rac activation and lymphocyte migration, PLoS One, 2012.09.
43. Nishikimi A, Uruno T, Duan X, Cao Q, Okamura Y, Saitoh N, Sakaoka S, Du Y, Suenaga A, Kukimoto-NIino M, Miyano K, Okabe T, Sanematsu F, Tanaka Y, Sumimoto H, Honma T, Yokoyama S, Nagano T, Kohda D, Kanai M, Fukui Y, Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2., Chem. Biol., 19, 488-497, 2012.04.
44. Harada Y, Tanaka Y, Terasawa M, Pieczyk M, Habiro K, Katakai T, Hanawa-Suetsugu K, Kukimoto-Niino M, Nishizaki T, Shirousu M, Duan X, Uruno T, Nishikimi A, Sanematsu F, Yokoyama S, Stein JV, Kinashi T, Fukui Y , DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses, Blood, 119, 4451-4461, 2012.03, 樹状細胞は、抗原に暴露されると輸入リンパ管を介してリンパ節に移動し、T 細胞に抗原を提示することで免疫応答を惹起する。樹状細胞は、三次元微小環境下では、二次元環境と異なり、インテグリン非依存的に細胞外マトリックスの隙間を形を変えながら進んでいくが、このアメーバ様運動を制御するシグナル伝達機構やスペースを感知するメカニズムは明らかではない。私達は、ヒト免疫不全症の責任分子として近年注目を集めているDOCK8の機能を、ノックアウトマウスを作製することで解析した。その結果、DOCK8欠損樹状細胞ではリンパ節へのホーミングが障害されており、T細胞を効率よく活性化できないことを見いだした。DOCK8欠損樹状細胞は二次元環境では正常に運動できるにも関わらず、三次元微小環境下での運動が顕著に障害されていた。DOCK8はCdc42特異的なGEFとして機能しており、その複合体の構造を決定すると共に、FRETを用いて、DOCK8がCdc42活性化の場の制御に重要な役割を演じることを明らかにした。.
45. Hanawa-Suetugu K, Kukimoto-Niino M, Mishima-Tsumagari C, Akasaka R, Ohsawa N, Sekine S, Ito T, Tochio N, Koshiba S, Kigawa T, Terada T, Shirouzu M, Nishikimi A, Uruno T, Katakai T, Kinishi T, Kohda D, Fukui Y, Yokoyama S, Structural basis for mutual relief of the Rac guanine nucleotide exchange factor DOCK2 and its partner ELMO1 from their autoinhibited forms., Proc. Natl. Acad. Sci. USA, 109, 9, 3305-3310, 2012.02.
46. Ippagunta SK, Subbarao Malireddi RK, Shaw PJ, Neal GA, Walle LV, Green DR, Fukui Y, Lamkanfi M, Kanneganti T-D, The inflammasome adaptor ASC regulates the function of adaptive immune cells by controlling Dock2-mediated Rac activation and actin polymerization., Nature Immunology, 2011.09.
47. Sanematsu F, Hirashima M, Laurin M, Takii R, Nishikimi A, Kitajima K, Ding G, Noda M, Murata Y, Tanaka Y, Masuko S, Suda T, Meno C, Côté JF, Nagasawa T, Fukui Y, DOCK180 is a Rac activator that regulates cardiovascular development by acting downstream of CXCR4., Circ. Res., 107:1102-1105, 2010.10.
48. Gotoh K, Tanaka Y, Nishikimi A, Nakamura R, Yamada H, Maeda N, Ishikawa T, Hoshino K, Uruno T, Cao Q, Higashi S, Kawaguchi Y, Enjoji M, Takayanagi R, Kaisho T, Yoshikai Y, Fukui Y, Selective control of type I IFN induction by the Rac activator DOCK2 during TLR-mediated plasmacytoid dendritic cell activation, J. Exp. Med., 207: 721-730, 2010.04, 形質細胞様樹状細胞(pDC)は、微生物由来の核酸を細胞内に存在するTLR7/TLR9を介して認識することで、炎症性サイトカインのみならず、大量のI型インターフェロン(IFN)を産生することから、近年脚光を集めている細胞である。pDC活性化におけるDOCK2の役割を解析する目的で、種々のTLRリガンドでpDCを刺激したところ、DOCK2欠損pDCではIL-12p40、IL-6といった炎症性サイトカインは正常に産生されるにも関わらず、I型IFNの産生が著しく低下することを見出した。このメカニズムを詳細に解析することで、TLRによる抗原認識とは独立してDOCK2-Racシグナル伝達系が作動し、IKK-alphaの活性化を介して、I型IFN産生を選択的に制御するという、新しい制御機構の存在を明らかにした。.
49. Nishikimi A, Fukuhara H, Su W, Hongu T, Takasuga S, Mihara H, Cao Q, Sanematsu F, Kanai M, Hasegawa H, Tanaka Y, Shibasaki M, Kanaho Y, Sasaki T, Frohman MA, Fukui Y, , Sequential regulation of DOCK2 dynamics by two phospholipids during neutrophil chemotaxis, Science, 324:384-387, 2009.04.
50. Gollmer K, Asperti-Boursin F, Tanaka Y, Okkenhaug K, Vanhaesebroeck B, Peterson JR, Fukui Y, Donnadieu E, Stein JV, CCL21 mediates CD4+ T cell costimulation via a DOCK2/Rac-dependent pathway, Blood, 114(3) : 580-588, 2009.03.
51. Gotoh K, Tanaka Y, Nishikimi A, Inayoshi A, Enjoji M, Takayanagi R, Sasazuki T, Fukui Y, Differential requirement for DOCK2 in migration of plasmacytoid dendritic cells versus myeloid dendritic cells, Blood, 111(6), 2973-2976, 2008.03.
52. Tanaka Y, Hamano S, Gotoh K, Murata Y, Kunisaki Y, Nishikimi A, Takii R, Kawaguchi M, Inayoshi A, Masuko S, Himeno K, Sasazuki T, Fukui Y, T helper type 2 differentiation and intracellular trafficking of the interleukin 4 receptor-α subunit controlled by the Rac activator Dock2., Nature Immunol., 8,1067-1075, 2007.09.
53. Nombela-Arrieta C, Mempel TR, Soriano SF, Mazo I, Wymann MP, Hirsch E, Martínez-A C, Fukui Y, von Andrian UH, Stein JV, A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate-mediatsd egress, J. Exp. Med., 9: 121-128, 2007.03.
54. Handa Y, Suzuki M, Ohya K, Iwai H, Ishijima N, Koleske AJ, Fukui Y, Sasakawa C, Shignella IpgB1 promotes bacterial entry through the ELMO-Dock180 machinery., Nature Cell Biology, 9: 121-128, 2007.01.
55. García-Bernal D, Sotillo-Mallo E, Nombela-Arrieta C, Samaniego R, Fukui Y, Stein JV, Teixidó J, DOCK2 is required for chemokine-promoted human T lymphocyte adhesion under shear stress mediated by the integrin alpha4beta1., J. Immunol., 177: 5215-5225, 2006.10.
56. Kunisaki Y, Nishikimi A, Tanaka Y, Takii R, Noda M, Inayoshi A, Watanabe K, Sanematsu F, Sasazuki T, Sasaki T, Fukui Y, DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis., J. Cell Biol., 174: 647-652, 2006.04.
57. Kunisaki Y, Tanaka Y, Sanui T, Inayoshi A, Noda M, Nakayama T, Harada M, Taniguchi M, Sasazuki T, Fukui Y, DOCK2 is required in T cell precursors for development of Valpha14 natural killer T (NKT) cells., J. Immunol., 176: 4640-4645, 2006.04.
58. Shulman Z, Pasvolsky R, Woolf E, Grabovsky V, Feigelson SW, Erez N, Fukui Y, Alon R, DOCK2 regulates chemokine-triggered lateral lymphocyte motility but not transendothelial migration., Blood, 108: 2150-2158, 2006.04.
59. Jiang H, Pan F, Erickson LM, Jang MS, Sanui T, Kunisaki Y, Sasazuki T, Fukui Y, Deletion of DOCK2, a regulator of the actin cytoskeleton in lymphocytes, suppresses cardiac allograft rejection, J. Exp. Med, 10.1084/jem.20050911, 202, 8, 1121-1130, 202: 1121-1130, 2005.10.
60. Nombela-Arrieta C, Lacalle RA, Montoya M, Kunisaki Y, Megilas D, Marques M, Carrera AC, Manes S, Fukui Y, Martines-A C, Stein JV, Differential requirements of DOCK2 and phosphoinositide-3-kinase gamma during T and B lymphocyte homing, Immunity, 10.1016/j.immuni.2004.07.012, 21, 3, 429-441, 21: 429-441, 2004.09.
61. Kunisaki T, Masuko S, Noda M, Inayoshi A, Sanui T, Harada M, Sasazuki T, Fukui Y., Defective fetal liver erythropoiesis and T-lymphopoiesis in mice lacking phosphatidylserine receptor, Blood, 10.1182/blood-2003-09-3245, 103, 9, 3362-3364, 103:119-129, 2004.05.
62. Sanui T, Inayoshi A, Noda M, Iwata E, Oike M, Sasazuki T, Fukui Y, DOCK2 is essential for antigen-induced translocation of TCR and lipid rafts, but not PKC-q and LFA-1, in T cells, Immunity, 10.1016/S1074-7613(03)00169-9, 19, 1, 119-129, 19:119-129, 2003.01.
63. Sanui T, Inayoshi A, Noda M, Iwata E, Stein JV, Sasazuki T, Fukui Y, DOCK2 regulates Rac activation and cytoskeletal reorganization through the interaction with ELMO1, Blood, 10.1182/blood-2003-01-0173, 102, 8, 2948-2950, 102: 2948-2950, 2003.01.
64. Fukui Y, Hashimoto O, Sanui T, Oono T, Koga H, Abe M, Inayoshi A, Noda M, Oike M, Shirai T, Sasazuki T, Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration, Nature, 10.1038/35090591, 412, 6849, 826-831, 412: 826-831, 2001.01.
65. Oono T, Fukui Y, Masuko S, Hashimoto O, Ueno T, Sanui T, Inayoshi A, Noda M, Sata M, Sasazuki T, Organ-specific autoimmunity in mice whose T cell repertoire is shaped by a single antigenic peptide., J. Clin. Invest, 10.1172/JCI13256, 108, 11, 1589-1596, 108: 1589-1596, 2001.01.
66. Fukui Y, Oono T, Cabaniols JP, Nakao K, Hirokawa K, Inayoshi A, Sanui T, Kanellopoulos J, Iwata E, Noda M, Katsuki M, Kourilsky P, Sasazuki T, Diversity of T cell repertoire shaped by a single peptide ligand is critically affected by its amino acid residue at a T cell receptor-contact., Proc. Natl. Acad. Sci. USA, 10.1073/pnas.250470797, 97, 25, 13760-13765, 97:13760-13765, 2000.01.
67. Fukui Y, Ishimoto T, Utsuyama M, Gyotoku T, Koga T, Nakao K, Hirokawa K, Katsuki M, Sasazuki,, Positive and negative CD4+ thymocyte selection by a single MHC class II/peptide ligand affected by its expression level in the thymus, Immunity, 10.1016/S1074-7613(00)80283-6, 6, 4, 401-410, 6: 401-410, 1997.01.
68. Fukui Y, Hashimoto O, Inayoshi A, Gyotoku T, Sano T, Koga T, Gushima T, Sasazuki T, Highly restricted T cell repertoire shaped by a single major histocompatibility complex-peptide ligand in the presence of a single rearranged T cell receptor b chain., J. Exp. Med., 10.1084/jem.188.5.897, 188, 5, 897-907, 188:897-907, 1998.01.
69. Gapin L, Fukui Y, Kanellopoulos J, Sano T, Casrouge A, Malier V, Beaudoing E, Gautheret D, Claverie JM, Sasazuki T, Kourilsky P, Quantitative analysis of the T-cell repertoire by a single peptide/MHC complex, J. Exp. Med., 187: 1871-1883, 1998.01.
70. Yamamoto K, Fukui Y, Esaki Y, Inamitsu T, Sudo T, Yamane K, Kamikawaji N, Kimura A, Sasazuki T, Functional interaction between human histocompatibility leukocyte antigen (HLA) class II and mouse CD4 molecule in antigen recognition by T cells in HLA-DR and DQ transgenic mice., J. Exp. Med., 10.1084/jem.180.1.165, 180, 1, 165-171, 180: 165-171, 1994.01.
71. Todd JA, Fukui Y, Kitagawa T, Sasazuki T, The A3 allele of the HLA-DQA1 locus in associated with susceptibility to type 1 diabetes in Japanese. , Proc.Natl. Acad. Sci., 10.1073/pnas.87.3.1094, 87, 3, 1094-1098, 87:1094-1098, 1990.01.
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Classes: Genetics, Immunology