Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Yoshinori Fukui Last modified date:2024.05.24

Professor / Division of Immunogenetics / Department of Immunobiology and Neuroscience / Medical Institute of Bioregulation

1. Kirsti Hornigold, Martin J Baker, Polly A Machin, Stephen A Chetwynd, Anna-Karin Johnsson, Chiara Pantarelli, Priota Islam, Melanie Stammers, Laraine Crossland, David Oxley, Hanneke Okkenhaug, Simon Walker, Rachael Walker, Anne Segonds-Pichon, Yoshinori Fukui, Angeliki Malliri, Heidi C E Welch , The Rac-GEF Tiam1 controls integrin-dependent neutrophil responses., Front. Immunol., 2023.11, [URL].
2. Toyoshi Yanagihara, Kentaro Hata, Keisuke Matsubara, Kazufumi Kunimura, Kunihiro Suzuki, Kazuya Tsubouchi, Satoshi Ikegame, Yoshihiro Baba, Yoshinori Fukui, Isamu Okamoto, Mass cytometry analysis of B-cell populations in extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue of the lung., Ann Hematol., 102, 10, 2961, 2023.10, [URL].
3. Kentaro Hata, Toyoshi Yanagihara, Keisuke Matsubara, Kazufumi Kunimura, Daisuke Eto, Kunihiro Suzuki, Kazuya Tsubouchi, Satoshi Ikegame, Yoshinori Fukui, Isamu Okamoto, Altered macrophage phenotypes in a case of autoimmune pulmonary alveolar proteinosis., ERJ Open Research, 2023.09, [URL].
4. Yoshihiro Ueda , Koichiro Higasa, Yuji Kamioka, Naoyuki Kondo, Shunsuke Horitani, Yoshiki Ikeda Wolfgang Bergmeier, Yoshinori Fukui, Tatsuo Kinashi, Rap1 organizes lymphocyte front-back polarity via RhoA signaling and talin1., iScience, 26, 8, 2023.08, [URL].
5. Polly A. Machin, Anna-Karin E. Johnsson, Ellie J. Massey, Chiara Pantarelli, Stephen A. Chetwynd, Julia Y. Chu, Hanneke Okkenhaug, Anne Segonds-Pichon, Simon Walker, Angeliki Malliri, Yoshinori Fukui, Heidi C. E. Welch, Dock2 generates characteristic spatiotemporal patterns of Rac activity to regulate neutrophil polarisation, migration and phagocytosis., Front. Immunol., 2023.06, [URL].
6. Mutsuko Kukimoto-Niino, Kentaro Ihara, Chiemi Mishima-Tsumagari, Mio Inoue, Yoshinori Fukui, Shigeyuki Yokoyama, Mikako Shirouzu, Structural basis for the dual GTPase specificity of the DOCK10 guanine nucleotide exchange factor., Biochem. Biophys. Res. Commun., 2023.04, [URL].
7. 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, 2023.03, [URL].
8. Kentaro Hata, Toyoshi Yanagihara, Keisuke Matsubara, Kazufumi Kunimura, Kunihiro Suzuki , Kazuya Tsubouchi, Daisuke Eto, Hiroyuki Ando , Maki Uehara , Satoshi Ikegame , Yoshihiro Baba , Yoshinori Fukui , Isamu Okamoto, Mass cytometry identifies characteristic immune cell subsets in bronchoalveolar lavage fluid from interstitial lung diseases., Front. Immunol., 2023.03, [URL].
9. 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., 2023.03, [URL].
10. Toyoshi Yanagihara, Kentaro Hata, Keisuke Matsubara, Kazufumi Kunimura, Kunihiro Suzuki, Kazuya Tsubouchi, Satoshi Ikegame, Yoshihiro Baba, Yoshinori Fukui, Isamu Okamoto, Exploratory mass cytometry analysis reveals immunophenotypes of cancer treatment-related pneumonitis., bioRxiv, 2023.02, [URL].
11. 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., 2023.02, [URL], Background: Drug-induced anaphylaxis is triggered by the direct stimulation of mast cells (MCs) via Mas-related G protein?coupled receptor X2 (MRGPRX2; mouse ortholog MRGPRB2). However, the precise mechanism that links MRGPRX2/B2 to MC degranulation is poorly understood. Dedicator of cytokinesis 2 (DOCK2) is a Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 regulates migration and activation of leukocytes, its role in MCs remains unknown. Objective: We aimed to elucidate whether?and if so, how?DOCK2 is involved in MRGPRX2/B2-mediated MC degranulation and anaphylaxis. Methods: Induction of drug-induced systemic and cutaneous anaphylaxis was compared between wild-type and DOCK2-deficient mice. In addition, genetic or pharmacologic inactivation of DOCK2 in human and murine MCs was used to reveal its role in MRGPRX2/B2-mediated signal transduction and degranulation. Results: Induction of MC degranulation and anaphylaxis by compound 48/80 and ciprofloxacin was severely attenuated in the absence of DOCK2. Although calcium influx and phosphorylation of several signaling molecules were unaffected, MRGPRB2-mediated Rac activation and phosphorylation of p21-activated kinase 1 (PAK1) were impaired in DOCK2-deficient MCs. Similar results were obtained when mice or MCs were treated with small-molecule inhibitors that bind to the catalytic domain of DOCK2 and inhibit Rac activation. Conclusion: DOCK2 regulates MRGPRX2/B2-mediated MC degranulation through Rac activation and PAK1 phosphorylation, thereby indicating that the DOCK2-Rac-PAK1 axis could be a target for preventing drug-induced anaphylaxis..
12. 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, 2022.08, [URL], Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1,2,3,4,5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n?=?61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target..
13. 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, 2022.07, [URL], Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by recurrent eczematous lesions, intense itch, and type 2 immune responses. Interleukin 31 (IL-31) is a cytokine mainly produced from skin-homing CLA+ T cells. IL-31 plays a major role in AD pathogenesis. Dedicator of cytokinesis 8 (DOCK8) is an evolutionarily conserved guanine nucleotide exchange factor (GEF) for Cdc42. Bi-allelic loss-of-function mutations of DOCK8 cause a combined immunodeficiency characterized by AD. We have previously shown that knock down of DOCK8 gene in T cells from healthy controls markedly increases T-cell receptor-mediated IL31 gene expression. Therefore, DOCK8 acts as a negative regulator for IL-31 induction in human T cells. However, DOCK8 expression is comparable between healthy controls and AD patients, and functional significance of DOCK8 in the disease predisposition remains unknown. In this study, we found that DOCK8 polymorphism at position 1790 (rs17673268) is associated with the susceptibility to AD and revealed its underlying molecular basis. Although this study used a relatively small sample size, our findings provide a novel insight into AD pathogenesis..
14. 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., 2022.06, [URL].
15. 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. , 2022.04, [URL].
16. Kazufumi Kunimura, Yoshinori Fukui, The molecular basis for IL-31 production and IL-31-mediated itch transmission: from biology to drug development., Int. Immunol., 33, 736, 2021.09, [URL].
17. 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., 559, 140, 2021.06, [URL].
18. 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., 148, 638-in press, 2021.04, [URL], 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..
19. 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. , 33, 160, 2021.03, [URL].
20. 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, 4, 4, e202000873, 2021.02, [URL].
21. Tomoaki Koga, Fumiyuki Sasaki, Kazuko Saeki, Soken Tsuchiya, Toshiaki Okuno, Mai Ohba, Takako Ichiki, Satoshi Iwamoto, Hirotsugu Uzawa, Keiko Kitajima, Chikara Meno, Eri Nakamura, Norihiro Tada, Yoshinori Fukui, Junichi Kikuta, Masaru Ishii, Yukihiko Sugimoto, Mitsuyoshi Nakao, Takehiko Yokomizo, Expression of leukotriene B4 receptor 1 defines functionally distinct DCs that control allergic skin inflammation., Cell. Mol. Immunol. , 18, 1449, 2020.09, [URL].
22. Fumiko Okumura, Yuha Fujiki, Nodoka Oki, Kana Osaki, Akihiko Nishikimi, Yoshinori Fukui, Kunio Nakatsukasa, Takumi Kamura, Cul5-type ubiquitin ligase KLHDC1 contributes to the elimination of truncated SELEONS produced by failed UGA/Sec decoding., iScience, 23, 3, 100970, 2020.03, [URL].
23. 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., 26, 9, 28340000000, 2019.11, [URL].
24. 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., 144, 4, 113300000000, 2019.10, [URL], 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..
25. Kazufumi Kunimura, Takehito Uruno, Yoshinori Fukui, DOCK-family proteins : key players in immune surveillance mechanisms, Int. Immunol., 2019.10, [URL].
26. Kazuhito Gotou, Takafumi Morisaki, Daiki Setoyama, Katsuhiko Sasaki, Mikako Yagi, Ko Igami, Soichi Mizuguchi, Takeshi Uchiumi, Yoshinori Fukui, Dongchon Kang, Mitochondrial p32/C1qbp Is a Critical Regulator of Dendritic Cell Metabolism and Maturation, Cell Rep., 25, 7, 1800-1815.e4, 18150000, 2018.11, [URL], Dendritic cell (DC) maturation induced by Toll-like receptor agonists requires activation of downstream signal transduction and metabolic changes. The endogenous metabolite citrate has recently emerged as a modulator of DC activation. However, the metabolic requirements that support citrate production remain poorly defined. Here, we demonstrate that p32/C1qbp, which functions as a multifunctional chaperone protein in mitochondria, supports mitochondrial metabolism and DC maturation. Metabolic analysis revealed that the citrate increase induced by lipopolysaccharide (LPS) is impaired in p32-deficient DCs. We also found that p32 interacts with dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase [PDH] complex) and positively regulates PDH activity in DCs. Therefore, we suggest that DC maturation is regulated by citrate production via p32-dependent PDH activity. p32-null mice administered a PDH inhibitor show decreased DC maturation and ovalbumin-specific IgG production in vivo, suggesting that p32 may serve as a therapeutic target for DC-related autoimmune diseases. Although mitochondrial metabolic pathways are essential for DC activation, the precise molecular mechanism remains poorly understood. Gotoh et al. show that mitochondrial p32/C1qbp supports dendritic cell metabolism and maturation. In addition, mitochondrial p32 and pyruvate dehydrogenase activity are necessary for DC maturation in vitro and in vivo..
27. 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. , 11, 541, 2018.07, [URL], 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..
28. Takahiro Tomino, Hirotada Tajiri, Takaaki Tatsuguchi, Takahiro Shirai, Kounosuke Oisaki, Shigeki Matsunaga, Fumiyuki Sanematsu, Daiji Sakata, Tomoharu Yoshizumi, Yoshihiko Maehara, Motomu Kanai, Jean Fran?ois Cote, Yoshinori Fukui, Takehito Uruno, DOCK1 inhibition suppresses cancer cell invasion and macropinocytosis induced by self-activating Rac1 P29S mutation., Biochem. Biophys. Res. Commun., 497, 1, 298-304, 304, 2018.02, [URL], Rac1 is a member of the Rho family of small GTPases that regulates cytoskeletal reorganization, membrane polarization, cell migration and proliferation. Recently, a self-activating mutation of Rac1, Rac1P29S, has been identified as a recurrent somatic mutation frequently found in sun-exposed melanomas, which possesses increased inherent GDP/GTP exchange activity and cell transforming ability. However, the role of cellular Rac1-interacting proteins in the transforming potential of Rac1P29S remains unclear. We found that the catalytic domain of DOCK1, a Rac-specific guanine nucleotide exchange factor (GEF) implicated in malignancy of a variety of cancers, can greatly accelerate the GDP/GTP exchange of Rac1P29S. Enforced expression of Rac1P29S induced matrix invasion and macropinocytosis in wild-type (WT) mouse embryonic fibroblasts (MEFs), but not in DOCK1-deficient MEFs. Consistently, a selective inhibitor of DOCK1 that blocks its GEF function suppressed the invasion and macropinocytosis in WT MEFs expressing Rac1P29S. Human melanoma IGR-1 and breast cancer MDA-MB-157 cells harbor Rac1P29S mutation and express DOCK1 endogenously. Genetic inactivation and pharmacological inhibition of DOCK1 suppressed their invasion and macropinocytosis. Taken together, these results indicate that DOCK1 is a critical regulator of the malignant phenotypes induced by Rac1P29S, and suggest that targeting DOCK1 might be an effective approach to treat cancers associated with Rac1P29S mutation..
29. Miho Ushijima, Takehito Uruno, Akihiko Nishikimi, Fumiyuki Sanematsu, Yasuhisa Kamikaseda, Kazufumi Kunimura, Daiji Sakata, Takaharu Okada, Yoshinori Fukui, The rac activator DOCK2 mediates plasma cell differentiation and IgG antibody production., Front. Immunol., 9, FEB, 2018.02, [URL], A hallmark of humoral immune responses is the production of antibodies. This process involves a complex cascade of molecular and cellular interactions, including recognition of specific antigen by the B cell receptor (BCR), which triggers activation of B cells and differentiation into plasma cells (PCs). Although activation of the small GTPase Rac has been implicated in BCR-mediated antigen recognition, its precise role in humoral immunity and the upstream regulator remain elusive. DOCK2 is a Rac-specific guanine nucleotide exchange factor predominantly expressed in hematopoietic cells. We found that BCR-mediated Rac activation was almost completely lost in DOCK2-deficient B cells, resulting in defects in B cell spreading over the target cell-membrane and sustained growth of BCR microclusters at the interface. When wild-type B cells were stimulated in vitro with anti-IgM F(ab')2 antibody in the presence of IL-4 and IL-5, they differentiated efficiently into PCs. However, BCR-mediated PC differentiation was severely impaired in the case of DOCK2-deficient B cells. Similar results were obtained in vivo when DOCK2-deficient B cells expressing a defined BCR specificity were adoptively transferred into mice and challenged with the cognate antigen. In addition, by generating the conditional knockout mice, we found that DOCK2 expression in B-cell lineage is required to mount antigen-specific IgG antibody. These results highlight important role of the DOCK2-Rac axis in PC differentiation and IgG antibody responses..
30. 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, 73, 1, 29-36, 36, 2018.01, [URL], 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..
31. Soh Yamazaki, Yoshihiko Tanaka, Hiromitsu Araki, Akira Kohda, Fumiyuki Sanematsu, Tomoko Arasaki, Xuefeng Duan, Fumihito Miura, Takaharu Katagiri, Ryodai Shindo, Hiroyasu Nakano, Takashi Ito, Yoshinori Fukui, Shogo Endo, Hideki Sumimoto, The AP-1 transcription factor JunB is required for Th17 cell differentiation, Scientific Reports, 7, 1, 2017.12, [URL], Interleukin (IL)-17-producing T helper (Th17) cells are crucial for host defense against extracellular microbes and pathogenesis of autoimmune diseases. Here we show that the AP-1 transcription factor JunB is required for Th17 cell development. Junb-deficient CD4+ T cells are able to develop in vitro into various helper T subsets except Th17. The RNA-seq transcriptome analysis reveals that JunB is crucial for the Th17-specific gene expression program. Junb-deficient mice are completely resistant to experimental autoimmune encephalomyelitis, a Th17-mediated inflammatory disease, and naive T helper cells from such mice fail to differentiate into Th17 cells. JunB appears to activate Th17 signature genes by forming a heterodimer with BATF, another AP-1 factor essential for Th17 differentiation. The mechanism whereby JunB controls Th17 cell development likely involves activation of the genes for the Th17 lineage-specifying orphan receptors RORγt and RORα and reduced expression of Foxp3, a transcription factor known to antagonize RORγt function..
32. Fumihiko Okumura, Akiko Joo-Okumura, Keisuke Obara, Alexander Petersen, Akihiko Nishikimi, Yoshinori Fukui, Kunio Nakatsukasa, Takumi Kamura, Ubiquitin ligase SPSB4 diminishes cell repulsive responses mediated by EphB2, Molecular Biology of the Cell, 28, 24, 3532-3541, 3541, 2017.11, [URL], Eph receptor tyrosine kinases and their ephrin ligands are overexpressed in various human cancers, including colorectal malignancies, suggesting important roles in many aspects of cancer development and progression as well as in cellular repulsive responses. The ectodomain of EphB2 receptor is cleaved by metalloproteinases (MMPs) MMP-2/MMP-9 and released into the extracellular space after stimulation by its ligand. The remaining membraneassociated fragment is further cleaved by the presenilin-dependent γ-secretase and releases an intracellular peptide that has tyrosine kinase activity. Although the cytoplasmic fragment is degraded by the proteasome, the responsible ubiquitin ligase has not been identified. Here, we show that SOCS box-containing protein SPSB4 polyubiquitinates EphB2 cytoplasmic fragment and that SPSB4 knockdown stabilizes the cytoplasmic fragment. Importantly, SPSB4 down-regulation enhances cell repulsive responses mediated by EphB2 stimulation. Altogether, we propose that SPSB4 is a previously unidentified ubiquitin ligase regulating EphB2-dependent cell repulsive responses..
33. 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, 49, 10, 1437-1449, 1449, 2017.10, [URL], 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..
34. Toyoshi Yanagihara, Takahiro Tomino, Takehito Uruno, Yoshinori Fukui, Corrigendum to “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 489/1 (2017) 8?13] (S0006291X1730997X) (10.1016/j.bbrc.2017.05.113), Biochemical and Biophysical Research Communications, 491, 4, 2017.09, [URL], The authors regret to say that they found a minor mistake in their article..
35. Markus Ackerknecht, Kathrin Gollmer, Philipp Germann, Xenia Ficht, Jun Abe, Yoshinori Fukui, Jim Swoger, Jorge Ripoll, James Sharpe, Jens V. Stein, Antigen availability and DOCK2-driven motility govern CD4+ t cell interactions with dendritic cells in vivo, Journal of Immunology, 199, 2, 520-530, 530, 2017.07, [URL], Parenchymal migration of naive CD4+ T cells in lymph nodes (LNs) is mediated by the Rac activator DOCK2 and PI3Kg and is widely assumed to facilitate efficient screening of dendritic cells (DCs) presenting peptide-MHCs (pMHCs). Yet how CD4+ T cell motility, DC density, and pMHC levels interdependently regulate such interactions has not been comprehensively examined. Using intravital imaging of reactive LNs in DC-immunized mice, we show that pMHC levels determined the occurrence and timing of stable CD4+ T cell-DC interactions. Despite the variability in interaction parameters, ensuing CD4+ T cell proliferation was comparable over a wide range of pMHC levels. Unexpectedly, decreased intrinsic motility of DOCK22/2 CD4+ T cells did not impair encounters with DCs in dense paracortical networks and, instead, increased interaction stability, whereas PI3Kg deficiency had no effect on interaction parameters. In contrast, intravital and whole-organ imaging showed that DOCK2-driven T cell motility was required to detach from pMHClow DCs and to find rare pMHChigh DCs. In sum, our data uncover flexible signal integration by scanning CD4+ T cells, suggesting a search strategy evolved to detect low-frequency DCs presenting high cognate pMHC levels..
36. 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, 489, 1, 44055, 13, 2017.07, [URL], 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..
37. 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 Fran?ois C?t?, Shigeyuki Yokoyama, Motomu Kanai, Yoshinori Fukui, Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1, Cell Reports, 19, 5, 969-980, 980, 2017.05, [URL], 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..
38. Audrey Le Floc'h, Yoshihiko Tanaka, Niels S. Bantilan, Guillaume Voisinne, Gr?goire Altan-Bonnet, Yoshinori Fukui, Morgan Huse, Correction
Annular PIP3 accumulation controls actin architecture and modulates cytotoxicity at the immunological synapse [The Journal of Experimental Medicine, 210, 12, November 18, (2013) 2721-2737]doi 10.1084/jem.20131324, Journal of Experimental Medicine, 214, 4, 2017.04, [URL], The authors regret that in the original version of their paper, the middle blot for Rac2 in Fig. 2 C was incorrect. The legend remains correct, and the corrected figure appears below. The online HTML and PDF versions of this article have been corrected. The error only remains in the print version..
39. 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, 292, 6, 2191-2202, 2202, 2017.02, [URL], 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..
40. 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, 8, 2017.01, [URL], 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..
41. Zhiping Liu, Si Ming Man, Qifan Zhu, Peter Vogel, Sharon Frase, Yoshinori Fukui, Thirumala Devi Kanneganti, DOCK2 confers immunity and intestinal colonization resistance to Citrobacter rodentium infection, Scientific reports, 6, 2016.06, [URL], Food poisoning is one of the leading causes of morbidity and mortality in the world. Citrobacter rodentium is an enteric pathogen which attaches itself to enterocytes and induces attachment and effacing (A/E) lesions. The ability of the bacterium to cause infection requires subversion of the host actin cytoskeleton. Rac-dependent actin polymerization is activated by a guanine nucleotide exchange factor known as Dedicator of cytokinesis 2 (DOCK2). However, the role of DOCK2 in infectious disease is largely unexplored. Here, we found that mice lacking DOCK2 were susceptible to C. rodentium infection. These mice harbored increased levels of C. rodentium bacteria, showed more pronounced weight loss and inflammation-associated pathology, and were prone to bacterial dissemination to the systemic organs compared with wild-type mice. We found that mice lacking DOCK2 were more susceptible to C. rodentium attachment to intestinal epithelial cells. Therefore, our results underscored an important role of DOCK2 for gastrointestinal immunity to C. rodentium infection..
42. Fumihiko Okumura, Keiji Uematsu, Stuart D. Byrne, Mie Hirano, Akiko Joo-Okumura, Akihiko Nishikimi, Taro Shuin, Yoshinori Fukui, Kunio Nakatsukasa, Takumi Kamura, Parallel regulation of von Hippel-Lindau disease by pVHL-mediated degradation of B-Myb and hypoxia-inducible factor α, Molecular and cellular biology, 36, 12, 1803-1817, 1817, 2016.06, [URL], pVHL, the protein product of the von Hippel-Lindau (VHL) tumor suppressor gene, is a ubiquitin ligase that targets hypoxiainducible factor α (HIF-α) for proteasomal degradation. Although HIF-α activation is necessary for VHL disease pathogenesis, constitutive activation of HIF-α alone did not induce renal clear cell carcinomas and pheochromocytomas in mice, suggesting the involvement of an HIF-α-independent pathway in VHL pathogenesis. Here, we show that the transcription factor B-Myb is a pVHL substrate that is degraded via the ubiquitin-proteasome pathway and that vascular endothelial growth factor (VEGF)- and/or platelet-derived growth factor (PDGF)-dependent tyrosine 15 phosphorylation of B-Myb prevents its degradation. Mice injected with B-Myb knockdown 786-O cells developed dramatically larger tumors than those bearing control cell tumors. Microarray screening of B-Myb-regulated genes showed that the expression of HIF-α-dependent genes was not affected by B-Myb knockdown, indicating that B-Myb prevents HIF-α-dependent tumorigenesis through an HIF-α-independent pathway. These data indicate that the regulation of B-Myb by pVHL plays a critical role in VHL disease..
43. Keiji Uematsu, Fumihiko Okumura, Syunsuke Tonogai, Akiko Joo-Okumura, Dawit Hailu Alemayehu, Akihiko Nishikimi, Yoshinori Fukui, Kunio Nakatsukasa, Takumi Kamura, ASB7 regulates spindle dynamics and genome integrity by targeting DDA3 for proteasomal degradation, Journal of Cell Biology, 215, 1, 2016.01, [URL], Proper dynamic regulation of the spindle is essential for successful cell division. However, the molecular mechanisms that regulate spindle dynamics in mitosis are not fully understood. In this study, we show that Cullin 5-interacting suppressor of cytokine signaling box protein ASB7 ubiquitinates DDA3, a regulator of spindle dynamics, thereby targeting it for proteasomal degradation. The presence of microtubules (MTs) prevented the ASB7-DDA3 interaction, thus stabilizing DDA3. Knockdown of ASB7 decreased MT polymerization and increased the proportion of cells with unaligned chromosomes, and this phenotype was rescued by deletion of DDA3. Collectively, these data indicate that ASB7 plays a crucial role in regulating spindle dynamics and genome integrity by controlling the expression of DDA3..