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  • 1
    Online Resource
    Online Resource
    DUSP6 mediates T cell receptor-engaged glycolysis and restrains T FH cell differentiation
    Proceedings of the National Academy of Sciences ; 2018
    In:  Proceedings of the National Academy of Sciences Vol. 115, No. 34 ( 2018-08-21)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 115, No. 34 ( 2018-08-21)
    Abstract: Activated T cells undergo metabolic reprogramming and effector-cell differentiation but the factors involved are unclear. Utilizing mice lacking DUSP6 (DUSP6 −/− ), we show that this phosphatase regulates T cell receptor (TCR) signaling to influence follicular helper T (T FH ) cell differentiation and T cell metabolism. In vitro, DUSP6 −/− CD4 + T FH cells produced elevated IL-21. In vivo, T FH cells were increased in DUSP6 −/− mice and in transgenic OTII-DUSP6 −/− mice at steady state. After immunization, DUSP6 −/− and OTII-DUSP6 −/− mice generated more T FH cells and produced more antigen-specific IgG2 than controls. Activated DUSP6 −/− T cells showed enhanced JNK and p38 phosphorylation but impaired glycolysis. JNK or p38 inhibitors significantly reduced IL-21 production but did not restore glycolysis. TCR-stimulated DUSP6 −/− T cells could not induce phosphofructokinase activity and relied on glucose-independent fueling of mitochondrial respiration. Upon CD28 costimulation, activated DUSP6 −/− T cells did not undergo the metabolic commitment to glycolysis pathway to maintain viability. Unexpectedly, inhibition of fatty acid oxidation drastically lowered IL-21 production in DUSP6 −/− T FH cells. Our findings suggest that DUSP6 connects TCR signaling to activation-induced metabolic commitment toward glycolysis and restrains T FH cell differentiation via inhibiting IL-21 production.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1800076115
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2018
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  • 2
    Online Resource
    Online Resource
    Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 34 ( 2008-08-26), p. 12429-12434
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 34 ( 2008-08-26), p. 12429-12434
    Abstract: Tumor necrosis factor receptor 1-associated death domain protein (TRADD) is the core adaptor recruited to TNF receptor 1 (TNFR1) upon TNFα stimulation. In cells from TRADD-deficient mice, TNFα-mediated apoptosis and TNFα-stimulated NF-κB, JNK, and ERK activation are defective. TRADD is also important for germinal center formation, DR3-mediated costimulation of T cells, and TNFα-mediated inflammatory responses in vivo . TRADD deficiency does not enhance IFNγ-induced signaling. Importantly, TRADD has a novel role in TLR3 and TLR4 signaling. TRADD participates in the TLR4 complex formed upon LPS stimulation, and TRADD-deficient macrophages show impaired cytokine production in response to TLR ligands in vitro . Thus, TRADD is a multifunctional protein crucial both for TNFR1 signaling and other signaling pathways relevant to immune responses.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0806585105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
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    detail.hit.zdb_id: 1461794-8
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  • 3
    Online Resource
    Online Resource
    14-3-3σ regulates B-cell homeostasis through stabilization of FOXO1
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 4 ( 2011-01-25), p. 1555-1560
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 4 ( 2011-01-25), p. 1555-1560
    Abstract: 14-3-3σ regulates cytokinesis and cell cycle arrest induced by DNA damage but its role in the immune system is unknown. Using gene-targeted 14-3-3σ–deficient (i.e., KO) mice, we studied the role of 14-3-3σ in B-cell functions. Total numbers of B cells were reduced by spontaneous apoptosis of peripheral B cells. Upon B-cell antigen receptor engagement in vitro, KO B cells did not proliferate properly or up-regulate CD86. In response to T cell-independent antigens, KO B cells showed poor secretion of antigen-specific IgM. This deficit led to increased lethality of KO mice after vesicular stomatitis virus infection. KO B cells showed elevated total FOXO transcriptional activity but also increased FOXO1 degradation. Coimmunoprecipitation revealed that endogenous 14-3-3σ protein formed a complex with FOXO1 protein. Our results suggest that 14-3-3σ maintains FOXO1 at a consistent level critical for normal B-cell antigen receptor signaling and B-cell survival.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1017729108
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 4
    Online Resource
    Online Resource
    Crucial role for TNF receptor-associated factor 2 (TRAF2) in regulating NFκB2 signaling that contributes to autoimmunity
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 45 ( 2011-11-08), p. 18354-18359
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 45 ( 2011-11-08), p. 18354-18359
    Abstract: TNF receptor-associated factor 2 (TRAF2) is a key intracellular signaling mediator that acts downstream of not only TNFα but also various members of the TNFα superfamily. Here, we report that, despite their lack of TNFα signaling, TRAF2 −/− TNFα −/− mice develop an inflammatory disorder characterized by autoantibody accumulation and organ infiltration by T cells with the phenotypes of activated, effector, and memory cells. RAG1 −/− mice reconstituted with TRAF2 −/− TNFα −/− bone marrow cells showed increased numbers of hyperactive T cells and rapidly developed progressive and eventually lethal inflammation. No inflammation was observed in RAG1 −/− mice reconstituted with TRAF2 −/− TNFα −/− T-cell receptor β −/− or TRAF2 −/− TNFα −/− NFκB-induced kinase +/− bone marrow cells. The pathogenic TRAF2 −/− TNFα −/− T cells showed constitutive NFκB2p52 activation and produced elevated levels of T-helper 1 and T-helper 17 cytokines. Our results suggest that a regulatory circuit consisting of TRAF2–NFκB-induced kinase–NFκB2p52 is essential for the proper control of effector T-cell polarization and that loss of T-cell TRAF2 function induces constitutive NFκB2p52 activity that drives fatal autoimmune inflammation independently of TNFα signaling. The involvement of this regulatory circuit in controlling autoimmune responses highlights the delicate balance required to avoid paradoxical adverse events when implementing new targeted anti-inflammatory therapies.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1109427108
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
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  • 5
    Online Resource
    Online Resource
    Coding mutations in NUS1 contribute to Parkinson’s disease
    Proceedings of the National Academy of Sciences ; 2018
    In:  Proceedings of the National Academy of Sciences Vol. 115, No. 45 ( 2018-11-06), p. 11567-11572
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 115, No. 45 ( 2018-11-06), p. 11567-11572
    Abstract: Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson’s disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations ( MAD1L1 , NUP98 , PPP2CB , PKMYT1 , TRIM24 , CEP131 , CTTNBP2 , NUS1 , SMPD3 , MGRN1 , IFI35 , and RUSC2 ), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed that NUS1 harbors significantly more rare nonsynonymous variants ( P = 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies in Drosophila demonstrated that the loss of NUS1 could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identify NUS1 as a candidate gene for PD.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1809969115
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2018
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    HSP90β prevents aging-related cataract formation through regulation of the charged multivesicular body protein (CHMP4B) and p53
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 31 ( 2023-08)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 31 ( 2023-08)
    Abstract: Cataract is a leading ocular disease causing global blindness. The mechanism of cataractogenesis has not been well defined. Here, we demonstrate that the heat shock protein 90β (HSP90β) plays a fundamental role in suppressing cataractogenesis. HSP90β is the most dominant HSP in normal lens, and its constitutive high level of expression is largely derived from regulation by Sp1 family transcription factors. More importantly, HSP90β is significantly down-regulated in human cataract patients and in aging mouse lenses, whereas HSP90β silencing in zebrafish causes cataractogenesis, which can only be rescued by itself but not other HSP90 genes. Mechanistically, HSP90β can directly interact with CHMP4B, a newly-found client protein involved in control of cytokinesis. HSP90β silencing causes upregulation of CHMP4B and another client protein, the tumor suppressor p53. CHMP4B upregulation or overexpression induces excessive division of lens epithelial cells without proper differentiation. As a result, these cells were triggered to undergo apoptosis due to activation of the p53/Bak–Bim pathway, leading to cataractogenesis and microphthalmia. Silence of both HSP90β and CHMP4B restored normal phenotype of zebrafish eye. Together, our results reveal that HSP90β is a critical inhibitor of cataractogenesis through negative regulation of CHMP4B and the p53-Bak/Bim pathway.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2221522120
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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  • 7
    Online Resource
    Online Resource
    Telomeric transcripts stimulate telomere recombination to suppress senescence in cells lacking telomerase
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 9 ( 2014-03-04), p. 3377-3382
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 9 ( 2014-03-04), p. 3377-3382
    Abstract: In human somatic cells or yeast cells lacking telomerase, telomeres are shortened upon each cell division. This gradual shortening of telomeres eventually leads to senescence. However, a small population of telomerase-deficient cells can survive by bypassing senescence through the activation of alternative recombination pathways to maintain their telomeres. Although genes involved in telomere recombination have been identified, mechanisms that trigger telomere recombination are less known. The THO (suppressor of the transcriptional defects of Hpr1 mutants by overexpression) complex is involved in transcription elongation and mRNA export. Here we demonstrate that mutations in THO complex components can stimulate early senescence and type II telomere recombination in cells lacking telomerase. The accumulation of telomere-associated noncoding telomere repeat-containing RNA (TERRA) is required for the observed telomere effects in THO complex mutants; reduced transcriptional efficiency, or overexpression of RNase H or C 1–3 A RNA can severely impair the type II telomere recombination. The results highlight a unique function for telomere-associated TERRA, in the formation of type II survivors. Moreover, because TERRA is a long noncoding RNA, these results reveal a function for long noncoding RNA in regulating recombination.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1307415111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
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    SSG: 12
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  • 8
    Online Resource
    Online Resource
    A High-Efficiency Power Cycle in Which Hydrogen Is Compressed by Absorption in Metal Hydrides
    American Association for the Advancement of Science (AAAS) ; 1976
    In:  Science Vol. 193, No. 4250 ( 1976-07-23), p. 314-317
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 193, No. 4250 ( 1976-07-23), p. 314-317
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.193.4250.314
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 1976
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    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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  • 9
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    Online Resource
    Childhood cancer chemotherapy–induced bone damage: pathobiology and protective effects of resveratrol and other nutraceuticals
    Wiley ; 2017
    In:  Annals of the New York Academy of Sciences Vol. 1403, No. 1 ( 2017-09), p. 109-117
    Details
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 1403, No. 1 ( 2017-09), p. 109-117
    Abstract: Intensive cancer chemotherapy causes significant bone loss, for which the mechanisms remain unclear and effective treatments are lacking. This is a significant issue particularly for childhood cancers, as the most common ones have a 〉 75% cure rate following chemotherapy; there is an increasing population of survivors who live with chronic bone defects. Studies suggest that these defects are the result of reduced bone from increased marrow fat formation and increased bone resorption following chemotherapy. These changes probably result from altered expression/activation of regulatory molecules or pathways regulating skeletal cell formation and activity. Treatment with methotrexate, an antimetabolite commonly used in childhood oncology, has been shown to increase levels of proinflammatory/pro‐osteoclastogenic cytokines (e.g., enhanced NF‐κB activation), leading to increased osteoclast formation and bone resorption, as well as to attenuate Wnt signaling, leading to both decreased bone and increased marrow fat formation. In recent years, understanding the mechanisms of action and potential health benefits of selected nutraceuticals, including resveratrol, genistein, icariin, and inflammatory fatty acids, has led to preclinical studies that, in some cases, indicate efficacy in reducing chemotherapy‐induced bone defects. We summarize the supporting evidence.
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
    URL: Issue
    URL: Article
    DOI: 10.1111/nyas.2017.1403.issue-1
    DOI: 10.1111/nyas.13380
    RVK:
    TD 7650
    Language: English
    Publisher: Wiley
    Publication Date: 2017
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    detail.hit.zdb_id: 211003-9
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    SSG: 11
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  • 10
    Online Resource
    Online Resource
    Control of Follicle‐Stimulating Hormone and Luteinizing Hormone Release by Hypothalamic Peptidesa
    Wiley ; 1993
    In:  Annals of the New York Academy of Sciences Vol. 687, No. 1 ( 1993-05), p. 55-59
    Details
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 687, No. 1 ( 1993-05), p. 55-59
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
    URL: Issue
    URL: Article
    DOI: 10.1111/nyas.1993.687.issue-1
    DOI: 10.1111/j.1749-6632.1993.tb43853.x
    RVK:
    TD 7650
    Language: English
    Publisher: Wiley
    Publication Date: 1993
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    detail.hit.zdb_id: 211003-9
    detail.hit.zdb_id: 2071584-5
    SSG: 11
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