担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Tau aggregates in neurons of brain lesions is a hallmark pathology of tauopathies, including Alzheimer's disease (AD). Recent studies suggest that the RNA-binding protein TIA1 initiates Tau aggregation by inducing the formation of stress granules (SGs) containing Tau. SGs are stress-inducible cytoplasmic protein aggregates containing many RNA-binding proteins that has been implicated as an initial site of multiple pathogenic protein aggregates in several neurodegenerative diseases. In this study, we found that ubiquitin-specific protease 10 (USP10) is a critical factor for the formation of Tau/TIA1/USP10-positive SGs. Proteasome inhibition or TIA1-overexpression in HT22 neuronal cells induced the formation of TIA1/Tau-positive SGs, and the formations were severely attenuated by depletion of USP10. In addition, the overexpression of USP10 without stress stimuli in HT22 cells induced TIA1/Tau/USP10-positive SGs in a deubiquitinase-independent manner. In AD brain lesions, USP10 was colocalized with Tau aggregates in the cell body of neurons. The present findings suggest that USP10 plays a key role in the initiation of pathogenic Tau aggregation in AD through SG formation.

DOI： 10.1038/s41598-019-47033-7

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その他リンク： http://www.nature.com/articles/s41598-019-47033-7

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

<title>Abstract</title>
The aberrant accumulation of ubiquitinated protein aggregates in cells plays a critical role in the pathogenesis of several degenerative diseases, including Parkinson disease (PD) and cystic fibrosis (CF). In this study, we found that Ras GTPase-activating protein-binding protein 1 (G3BP1) inhibits ubiquitinated protein aggregations induced by p62 and USP10 in cultured cells. p62 is a ubiquitin receptor, and p62 and its binding partner USP10 have been shown to augment ubiquitinated protein aggregation. G3BP1 interacted with p62 and USP10 and inhibited p62/USP10-induced protein aggregation. The G3BP1 inhibition of protein aggregations targeted two aggregation-prone proteins, α-synuclein and CFTR-ΔF508, which are causative factors of PD and CF, respectively. G3BP1 depletion increased the amounts of ubiquitinated α-synuclein and CFTR-ΔF508 protein. A proteasome reporter indicated that G3BP1 depletion inhibits the proteasome activity. We herein present evidence that G3BP1, p62 and USP10 together control ubiquitinated protein toxicity by controlling both ubiquitination and aggregation. Taken together, these results suggest that G3BP1, p62 and USP10 could be therapeutic targets for ubiquitinated protein aggregation disorders, including PD and CF.

DOI： 10.1038/s41598-019-46237-1

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その他リンク： http://www.nature.com/articles/s41598-019-46237-1

担当区分：筆頭著者   記述言語：日本語  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

Accumulation of ubiquitinated proteins is cytotoxic, but cells inactivate these cytotoxicities by inducing aggresome formation. We found that ubiquitin-specific protease 10 (USP10) inhibits ubiquitinated protein-induced apoptosis by inducing aggresome formation. USP10 interacted with the ubiquitin receptor p62 and the interaction augmented p62-dependent ubiquitinated protein aggregation and aggresome formation, thereby cooperatively inhibiting apoptosis. We provide evidence that USP10/p62-induced protein aggregates inhibit proteasome activity, which increases the amount of ubiquitinated proteins and promotes aggresome formation. USP10 induced aggresomes containing α-synuclein, a pathogenic protein in Parkinson disease, in cultured cells. In Parkinson disease brains, USP10 was colocalized with α-synuclein in the disease-linked aggresome-like inclusion Lewy bodies, suggesting that USP10 inhibits α-synuclein-induced neurotoxicity by promoting Lewy body formation. Collectively, these findings suggest that USP10 is a critical factor to control protein aggregation, aggresome formation, and cytotoxicity in protein-aggregation-related diseases.

DOI： 10.1016/j.isci.2018.11.006

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Membrane-associated guanylate kinase with inverted orientation protein 1 (MAGI-1) is a cytoplasmic scaffold protein that interacts with various signaling molecules; it negatively controls the cell growth of various types of cells and positively controls cell-cell interaction. In T cells, MAGI-1 has been shown to inhibit Akt activity through its interaction with PTEN and MEK1. In this study we found that MAGI-1 expression is decreased in multiple (9 out of 15) human T-cell leukemia cell lines, including adult T-cell leukemia (ATL), T-cell acute lymphoblastic leukemia and chronic T-cell lymphocytic leukemia. The overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced cellular growth. While the overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced the Akt and MEK activities, the knockdown of MAGI-1 in a MAGI-1-high ATL cell line augmented the Akt and MEK activities. Collectively, the findings of the present study suggest that the decreased expression of MAGI-1 in human T cells contributes to the development of several types of T-cell leukemia, partly through the stimulation of the Akt and MEK pathways.

DOI： 10.1007/s12185-017-2359-1

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その他リンク： http://link.springer.com/content/pdf/10.1007/s12185-017-2359-1.pdf

掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.stemcr.2016.11.003

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s11262-015-1277-7

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その他リンク： http://link.springer.com/article/10.1007/s11262-015-1277-7/fulltext.html

掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/eji.201444977

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley Publishing Asia Pty Ltd  

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia (ATL), which is an aggressive form of T-cell malignancy. HTLV-1 oncoproteins, Tax and HBZ, play crucial roles in the immortalization of T-cells and/or leukemogenesis by dysregulating the cellular functions in the host. Recent studies show that HTLV-1-infected T-cells have reduced expression of the BCL11B tumor suppressor protein. In the present study, we explored whether Tax and/or HBZ play a role in downregulating BCL11B in HTLV-1-infected T-cells. Lentiviral transduction of Tax in a human T-cell line repressed the expression of BCL11B at both the protein and mRNA levels, whereas the transduction of HBZ had little effect on the expression. Tax mutants with a decreased activity for the NF-κB, CREB or PDZ protein pathways still showed a reduced expression of the BCL11B protein, thereby implicating a different function of Tax in BCL11B downregulation. In addition, the HTLV-2 Tax2 protein reduced the BCL11B protein expression in T-cells. Seven HTLV-1-infected T-cell lines, including three ATL-derived cell lines, showed reduced BCL11B mRNA and protein expression relative to an uninfected T-cell line, and the greatest reductions were in the cells expressing Tax. Collectively, these results indicate that Tax is responsible for suppressing BCL11B protein expression in HTLV-1-infected T-cells; Tax-mediated repression of BCL11B is another mechanism that Tax uses to promote oncogenesis of HTLV-1-infected T-cells.

DOI： 10.1111/cas.12618

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.12618

掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/cam4.329

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cam4.329

担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society of Hematology  

<title>Key Points</title>
Interaction of HTLV-1 Tax with USP10 reduces arsenic-induced stress granule formation and enhances ROS production. USP10 controls sensitivities of leukemia cell lines to arsenic-induced apoptosis.

DOI： 10.1182/blood-2013-03-493718

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/cas.12087

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society for Microbiology  

DOI： 10.1128/mcb.00763-12

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/gtc.12023

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s11262-012-0831-9

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その他リンク： http://link.springer.com/article/10.1007/s11262-012-0831-9/fulltext.html

掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

DOI： 10.3389/fmicb.2013.00328

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/j.1349-7006.2011.02123.x

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s11262-009-0447-x

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その他リンク： http://link.springer.com/article/10.1007/s11262-009-0447-x/fulltext.html

掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society of Hematology  

<title>Abstract</title>Adult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). The activation of NF-κB by Tax has been reported to play a crucial role in HTLV-1–induced transformation. The HTLV-1 bZIP factor (HBZ), which is encoded by an mRNA of the opposite polarity of the viral genomic RNA, is involved in both T cell proliferation and suppression of Tax-mediated viral gene transcription, suggesting that HBZ cooperates closely with Tax. In the present study, we observed that HBZ specifically suppressed NF-κB–driven transcription mediated by p65 (the classical pathway) without inhibiting the alternative NF-κB signaling pathway. In an immunoprecipitation assay, HBZ bound to p65 and diminished the DNA binding capacity of p65. In addition, HBZ induced p65 degradation through increasing the expression of the PDLIM2 gene, which encodes a ubiquitin E3 ligase for p65. Finally, HBZ actually repressed the transcription of some classical NF-κB target genes, such as IL-8, IL2RA, IRF4, VCAM-1, and VEGF. Selective suppression of the classical NF-κB pathway by HBZ renders the alternative NF-κB pathway predominant after activation of NF-κB by Tax or other stimuli, which might be critical for oncogenesis.

DOI： 10.1182/blood-2008-06-161729

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1186/1742-4690-6-83

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s11262-008-0259-4

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その他リンク： http://link.springer.com/article/10.1007/s11262-008-0259-4/fulltext.html

掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s11262-008-0234-0

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その他リンク： http://link.springer.com/article/10.1007/s11262-008-0234-0/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1349-7006.2008.00750.x

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掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society for Microbiology  

<title>ABSTRACT</title>
Human T-cell leukemia virus type 1 (HTLV-1) but not HTLV-2 is associated with adult T-cell leukemia, and the distinct pathogenicity of these two closely related viruses is thought to stem from the distinct biological functions of the respective transforming proteins, HTLV-1 Tax1 and HTLV-2 Tax2. In this study, we demonstrate that Tax1 but not Tax2 interacts with NF-κB2/p100 and activates it by inducing the cleavage of p100 into the active transcription factor p52. Using RNA interference methods, we further show that NF-κB2/p100 is required for the transformation induced by Tax1, as determined by the ability to convert a T-cell line (CTLL-2) from interleukin-2 (IL-2)-dependent to -independent growth. While Tax2 shows a reduced transforming activity relative to Tax1, Tax2 fused with a PDZ domain binding motif (PBM) present only in Tax1 shows transforming activity equivalent to that of Tax1 in CTLL-2 cells expressing an inducer of p52 processing. These results reveal that the activation of NF-κB2/p100 plays a crucial role in the Tax1-mediated transformation of T cells and that NF-κB2/p100 activation and PBM function are both responsible for the augmented transforming activity of Tax1 relative to Tax2, thus suggesting that these Tax1-specific functions play crucial roles in HTLV-1 leukemogenesis.

DOI： 10.1128/jvi.00532-07

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s11262-006-0048-x

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その他リンク： http://link.springer.com/article/10.1007/s11262-006-0048-x/fulltext.html

DOI： 10.1186/1742-4690-3-88

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/1742-4690-3-71

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society for Microbiology  

<title>ABSTRACT</title>
Human T-cell leukemia virus type 1 (HTLV-1) but not HTLV-2 is associated with adult T-cell leukemia. We found that HTLV-2 Tax2 protein stimulated reporter gene expression regulated by the interleukin (IL)-2 promoter through the nuclear factor of activated T cells (NFAT) in a human T-cell line (Jurkat). However, the activity of HTLV-1 Tax1 was minimal in this system. T-cell lines immortalized by HTLV-2 but not HTLV-1 constitutively exhibited activated NFAT in the nucleus and constitutively expressed IL-2 mRNA. Cyclosporine A, an inhibitor of NFAT activation, abrogated the induction of IL-2 mRNA in HTLV-2-immortalized T-cell lines and concomitantly inhibited cell growth. This growth inhibition was rescued by the addition of IL-2 to the culture. Furthermore, anti-IL-2 receptor antibodies significantly reduced the proliferation of HTLV-2-infected T-cell lines but not that of HTLV-1-infected cells. Our results suggest that Tax2 activates an IL-2 autocrine loop mediated through NFAT that supports the growth of HTLV-2-infected cells under low-IL-2 conditions. This mechanism would be especially important in vivo, where this autocrine mechanism establishes a nonleukemogenic life-long HTLV-2 infection. The results also suggest that differences in long-term cytokine production between HTLV-1 and HTLV-2 infection are another factor for the differences in pathogenesis.

DOI： 10.1128/jvi.79.18.11925-11934.2005

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.micinf.2004.09.014

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：社団法人日本獣医学会  

ヒツジにBLV tax遺伝子を高率に発現する分子クローン(high tax pBLV-IF)(H群, Nos. 1-5), 遺伝子改変を加えていないtax遺伝子を発現する分子クローン(wild tax pBLV-IF)(W群, Nos. 6-11)を接種し, 3頭(C群, No.12-14)を陰性対照群とし, 4ヵ月から46ヵ月間観察した.H群で5/5症例, W群で3/6症例(Nos. 6, 7, 9)がgp51抗体陽性を示した.H群は1症例のみで白血性病態を認め, H群, W群各1頭(Nos. 3, 6)にリンパ腫が発症した.No.3ではリンパ節, 第四胃以下の消化管, 心臓を始め多臓器に, No.6では空腸, 心臓のみにリンパ腫病変が認められた.腫瘍細胞の形態は両者ともに小型から中型のリンパ球様細胞が認められたが, No.3のみにリンパ芽球様細胞が認められた.免疫組織化学的検索により, 腫瘍細胞の表現型は両者共にCD1^-, CD4^-, CD5^-, CD8α^-, sIgM^+, λlight chain^+, B-B4^+, MHC class II^+であった.本研究により, pBLV-IF接種によってヒツジにリンパ腫およびリンパ性白血病が発症することが明らかになった.また, BLV tax遺伝子の転写効率の違いによるリンパ腫発症率には差異が認められない事が示唆された.

DOI： 10.1292/jvms.67.1231

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/1742-4690-2-29

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/1742-4690-2-46

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.micinf.2004.02.014

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）  

DOI： 10.1128/jvi.77.3.1894-1903.2003

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記述言語：日本語   出版者・発行元：(公社)日本獣医学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：MARY ANN LIEBERT INC PUBL  

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