Interferon regulatory factor-5 (IRF5), a transcription factor critical for the induction of innate immune responses, contributes to the pathogenesis of the autoimmune disease systemic lupus ...erythematosus (SLE) in humans and mice. Lyn, a Src family kinase, is also implicated in human SLE, and Lyn-deficient mice develop an SLE-like disease. Here, we found that Lyn physically interacted with IRF5 to inhibit ubiquitination and phosphorylation of IRF5 in the TLR-MyD88 pathway, thereby suppressing the transcriptional activity of IRF5 in a manner independent of Lyn’s kinase activity. Conversely, Lyn did not inhibit NF-κB signaling, another major branch downstream of MyD88. Monoallelic deletion of Irf5 alleviated the hyperproduction of cytokines in TLR-stimulated Lyn–/– dendritic cells and the development of SLE-like symptoms in Lyn–/– mice. Our results reveal a role for Lyn as a specific suppressor of the TLR-MyD88-IRF5 pathway and illustrate the importance of fine-tuning IRF5 activity for the maintenance of immune homeostasis.
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•Lyn binds to and inhibits the activity of IRF5 in the TLR-MyD88 pathway•Lyn inhibits post-translational modifications of IRF5 without Lyn’s kinase activity•Lyn deficiency causes IRF5 hyperactivation in DCs•SLE symptoms in Lyn–/– mice are ameliorated by monoallelic deletion of Irf5
How IRF5 activity is negatively regulated remains largely unknown. Tamura and colleagues identify Lyn as an IRF5-binding protein that suppresses the TLR-MyD88-IRF5 pathway. IRF5 is hyperactivated in Lyn-deficient mice suffering from the autoimmune disease SLE, but reducing the abundance of IRF5 ameliorates the disease development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Utilization of transcription factors might be a powerful approach to modification of metabolism for a generation of crops having superior characteristics because a single transcription factor ...frequently regulates coordinated expression of a set of key genes for respective pathways. Here, we apply the plant-specific Dof1 transcription factor to improve nitrogen assimilation, the essential metabolism including the primary assimilation of ammonia to carbon skeletons to biosynthesize amino acids and organic compounds involving nitrogen in plants. Expressing Dof1 induced the up-regulation of genes encoding enzymes for carbon skeleton production, a marked increase of amino acid contents, and a reduction of the glucose level in transgenic Arabidopsis. The results suggest cooperative modification of carbon and nitrogen metabolisms on the basis of their intimate link. Furthermore, elementary analysis revealed that the nitrogen content increased in the Dof1 transgenic plants (≈30%), indicating promotion of net nitrogen assimilation. Most significantly, the Dof1 transgenic plants exhibit improved growth under low-nitrogen conditions, an agronomically important trait. These results highlight the great utility of transcription factors in engineering metabolism in plants.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Abstract
The transcription factor interferon regulatory factor 5 (IRF5) is critical for innate immune responses downstream of Toll-like receptors (TLRs). IRF5 is also linked to the pathogenesis of ...systemic lupus erythematosus (SLE) in humans and mice. However, it remains elusive whether and how IRF5 activity can be negatively regulated. The Src family kinase Lyn is also implicated in human SLE, and Lyn−/− mice develop an SLE-like disease. Here we show that Lyn selectively inhibits IRF5 activity, while it does not affect the NF-κB pathway. Lyn physically interacted with IRF5, thereby suppressing the phosphorylation and ubiquitination of IRF5, post-translational modifications important for IRF5 activation. Interestingly, the kinase activity of Lyn was dispensable for the suppression of IRF5 activity. IRF5 was hyper-activated in TLR7/9-stimulated Lyn−/− bone marrow-derived dendritic cells (BMDCs), and these cells hyper-produced IRF5-dependent cytokines especially type-I interferons (IFNs). IRF5 was constitutively activated (phosphorylated and translocated into the nucleus) in splenic DCs isolated from Lyn−/− mice. Importantly, even monoallelic ablation of the Irf5 gene was sufficient to alleviate the hyper-production of type-I IFNs in TLR7/9-stimulated Lyn−/− BMDCs, and to ameliorate the development of SLE-like symptoms, such as autoantibody production and autoimmune glomerulonephritis, in Lyn−/− mice. Our results identify Lyn as a critical suppressor of the TLR-MyD88-IRF5 pathway, and implicate that the selective control of IRF5 activity may contribute to better therapeutics for SLE.
目的：近年，共同意思決定や活動・参加に焦点を当てた理学療法介入が注目されている。今回，本人の望む作業選択が可能となる作業選択意思決定支援ソフト（Aid for Decision-making in Occupation Choice ; ADOC）を用いて目標を設定し，目標に対する課題指向型トレーニング（Task-Oriented Training ; ...TOT）を通じて食事動作が改善した重症心身障害を有する成人の一例を報告する。症例と経過：症例は重症心身障害児者施設に入所している20代の男性である。今回，本人にiPadを提示し，ADOCのイラストから本人のやりたい作業の選択を行った。そして生活支援を行う介護福祉士や保育士らと得られた情報を共有し，食事動作に対する反復的なTOTを日常生活内で2か月間実施した。結果，食事動作にて客観的・主観的双方における改善を認めた。結論：ADOCを用いて共同で目標設定を行い，目標に対するTOTを協働で，日常的に実施したことで，食事動作に改善が見られた症例を経験した。
The encoding extrinsic 12-kDa protein of oxygen-evolving PS II complex from a red alga, Cyanidium caldarium, was cloned and sequenced by means of PCR and a rapid amplification of cDNA ends (RACE) ...procedure. The gene encodes a putative polypeptide of 154 amino acids with a calculated molecular mass of 16,714 Da. The full sequence of the protein includes two characteristic transit peptides, one for transfer across the chloroplast envelope and another for targeting into the thylakoid lumen. This indicates that the protein is encoded in the nuclear genome. The mature protein consists of 93 amino acids with a calculated molecular mass of 10,513 Da. The cloned gene was successfully expressed in Escherichia coli and the resulting protein was purified, reconstituted to CaCl2-washed PS II complex together with the other extrinsic proteins of 33 and 20 kDa and cyt c-550. The recombinant 12-kDa protein bound completely with the PSII complex, which resulted in a restoration of oxygen evolution equal to the level achieved by binding of the native 12-kDa protein.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The 33kDa protein of photosystem II (PSII) is common to all of the organisms and totally exchangeable in binding to PSII from various different organisms (Enami et al. , 2000, Plant Cell Physiol. 41, ...1354-1364). The amino acid sequence of the 33kDa protein showed a relatively high homology above 40% from cyanobacteria to higher plants. Thus, the structure of the 33kDa protein has been considered to be conserved during evolution from cyanobacteria to higher plants. In this study, reconstitution experiments were performed for the extrinsic 23 and l7kDa proteins from spinach with spinach PSII which had been exchanged for the 33kDa protein from different sources. Spinach PSII was treated with 2. 6 M urea/0. 2 M NaCl to remove all of the extrinsic proteins, and then reconstituted with the 33kDa protein from a cyanobacterium (Synechococcus vulcanus), a red alga (Gyanidium caldarium), a higher plant (Spinach). The results showed that spinach PSII which had been exchanged for the red algal or cyanobacterial 33kDa protein partially rebound the 23kDa protein but totally failed to bind the l7kDa protein, although the PSII bearing its own 33kDa protein retained the full ability to bind the 23 and l7kDa proteins. This suggests that the 33kDa protein has a different structure between higher plants and red algae or cyanobacteria, at least from the viewpoint of its interaction with other extrinsic proteins.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Ovarian cancer is the fifth most common cause of cancer‐related death in women. Ovarian clear cell carcinoma (OCCC) is a chemotherapy‐resistant epithelial ovarian cancer with poor prognosis. As a ...basis for the development of therapeutic agents that could improve the prognosis of OCCC, we performed a screen for proteins critical for the tumorigenicity of OCCC using the CRISPR/Cas9 system. Here we show that knockdown of the phosphate exporter XPR1/SLC53A1 induces the growth arrest and apoptosis of OCCC cells in vitro. Moreover, we show that knockdown of XPR1/SLC53A1 inhibits the proliferation of OCCC cells xenografted into immunocompromised mice. These results suggest that XPR1/SLC53A1 plays a critical role in the tumorigenesis of OCCC cells. We speculate that XPR1/SLC53A1 might be a promising molecular target for the therapeutic treatment of OCCC.
We attempted to identify novel molecular targets critical for the proliferation and tumorigenicity of ovarian clear cell carcinoma (OCCC) using the CRISPR/Cas9 system. In this study, we have found that the phosphate exporter XPR1/SLC53A1 plays an important role in the proliferation and tumorigenicity of OCCC. Our results suggest that XPR1/SLC53A1 might be a promising molecular target for the therapeutic treatment of OCCC.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Despite the frequent detection of
KRAS
driver mutations in patients with colorectal cancer (CRC), no effective treatments that target mutant KRAS proteins have been introduced into clinical practice. ...In this study, we identified potential effector molecules, based on differences in gene expression between CRC patients carrying wild-type
KRAS
(
n
= 390) and those carrying
KRAS
mutations in codon 12 (
n
= 240). CRC patients with wild-type
KRAS
harboring mutations in
HRAS
,
NRAS
,
PIK3CA
,
PIK3CD
,
PIK3CG
,
RALGDS
,
BRAF,
or
ARAF
were excluded from the analysis. At least 11 promising candidate molecules showed greater than two-fold change between the
KRAS
G12 mutant and wild-type and had a Benjamini-Hochberg-adjusted
P
value of less than 1E-08, evidence of significantly differential expression between these two groups. Among these 11 genes examined in cell lines transfected with
KRAS
G12 mutants,
BMP4
,
PHLDA1,
and
GJB5
showed significantly higher expression level in
KRAS
G12A, G12D, and G12V transfected cells than in the wild-type transfected cells. We expect that this study will lead to the development of novel treatments that target signaling molecules functioning with
KRAS
G12-driven CRC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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