The Histidine Transporter SLC15A4 Coordinates mTOR-Dependent Inflammatory Responses and Pathogenic Antibody Production

Kobayashi, Toshihiko; Shimabukuro-Demoto, Shiho; Yoshida-Sugitani, Reiko; Furuyama-Tanaka, Kaori; Karyu, Hitomi; Sugiura, Yuki; Shimizu, Yukiko; Hosaka, Toshiaki; Goto, Motohito; Kato, Norihiro; Okamura, Tadashi; Suematsu, Makoto; Yokoyama, Shigeyuki; Toyama–Sorimachi, Noriko

doi:10.1016/j.immuni.2014.08.011

Cited by 131 publications

(171 citation statements)

References 47 publications

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“…Expression of SLC15A4, a histidine transporter, was previously observed in the gastrointestinal tract (54). This histidine transporter coordinates mechanistic target of rapamycin-dependent inflammatory responses and may promote colitis (55,56). In the present study, two early-stage CRC cell lines, SW1116 and LS123, exhibited a higher expression level of SLC15A4 than normal colonic cells and late-stage CRC cell lines.…”

Section: Discussionsupporting

confidence: 60%

Discovery of genes from feces correlated with colorectal cancer progression

et al. 2016

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Abstract. Colorectal cancer (CRC) is considered to develop slowly via a progressive accumulation of genetic mutations. Markers of CRC may serve to provide the basis for decision-making, and may assist in cancer prevention, detection and prognostic prediction. DNA and messenger (m)RNA molecules that are present in human feces faithfully represent CRC manifestations. In the present study, exogenous mouse cells verified the feasibility of total fecal RNA as a marker of CRC. Furthermore, five significant genes encoding solute carrier family 15, member 4 (SLC15A4), cluster of differentiation (CD)44, 3-oxoacid CoA-transferase 1 (OXCT1), placenta-specific 8 (PLAC8) and growth arrest-specific 2 (GAS2), which are differentially expressed in the feces of CRC patients, were verified in different CRC cell lines using quantitative polymerase chain reaction. The present study demonstrated that the mRNA level of SLC15A4 was increased in the majority of CRC cell lines evaluated (SW1116, LS123, Caco-2 and T84). An increased level of CD44 mRNA was only detected in an early-stage CRC cell line, SW1116, whereas OXCT1 was expressed at higher levels in the metastatic CRC cell line CC-M3. In addition, two genes, PLAC8 and GAS2, were highly expressed in the recurrent CRC cell line SW620. Genes identified in the feces of CRC patients differed according to their clinical characteristics, and this differential expression was also detected in the corresponding CRC cell lines. In conclusion, feces represent a good marker of CRC and can be interpreted through the appropriate CRC cell lines. IntroductionColorectal cancer (CRC) is considered to develop slowly via the progressive accumulation of genetic mutations (1,2). Genes that regulate cell growth and differentiation must be altered in cancerous cells in the process of tumorigenesis (3,4). Markers of CRC may provide the basis for decision-making regarding intensive chemotherapy or molecule-targeting drugs in CRC patients (5-7). Therefore, the identification of markers may assist in cancer prevention, detection and prognostic prediction (5,8,9), thereby increasing survival rates (10). Molecular markers (11) have their own clinical significance in CRC (12).In CRC, both sigmoidoscopy and colonoscopy are considered to be the gold standards regarding detection rates. However, these clinical examinations have drawbacks in terms of their risk and inconvenience (13,14

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Section: Discussionsupporting

confidence: 60%

Discovery of genes from feces correlated with colorectal cancer progression

et al. 2016

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“…While this study provides compelling evidence that pDCs and their TLR7/TLR9-mediated responses are damaging in SLE, IRF8 and SLC15A4 are not exclusively expressed by pDCs. In fact, B cell expression of SLC15A4 appears to be necessary for TLR7-induced expression of type I IFN and pathogenic antibody production in a mouse model of lupus 189 . Analysis of MRL.…”

Section: Pathogenic Functions Of Pdcs In Autoimmunitymentioning

confidence: 99%

The multifaceted biology of plasmacytoid dendritic cells

2015

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Plasmacytoid dendritic cells (pDCs) are a unique dendritic cell subset that specializes in the production of type I interferons (IFNs). pDCs promote antiviral immune responses and have been implicated in the pathogenesis of autoimmune diseases characterized by a type I IFN signature. However, pDCs can also induce tolerogenic immune responses. Here, we review recent progress from the field of pDC biology, focusing on: the molecular mechanisms that regulate pDC development and functions; the pathways involved in their sensing of pathogens and endogenous nucleic acids; the function of pDCs at mucosal sites; and their roles in infections, autoimmunity and cancer.

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“…Based on recent work in B cells, SLC15A4 is necessary for endolysosomal acidification, and in the absence of this, TLR-initiated, mTOR-dependent, IFN-regulatory factor 7 (IRF7)-mediated type I IFN production is inhibited 66 . Moreover, autocrine signalling by type I IFNs through the IFNα/β receptor — which leads to further increased type I IFN production and the activation of additional genes, and is mTOR dependent — is also inhibited in Slc15a4 -deficient cells 66 . These data are consistent with the fact that mTORC1 localizes to lysosomes where it acts as sensor of lysosomal amino acid concentrations, which are an indicator of metabolic status 67 .…”

Section: Metabolism Of Activated Dcsmentioning

confidence: 99%

Dendritic cell metabolism

2014

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The past 15 years have seen enormous advances in our understanding of the receptor and signalling systems that allow dendritic cells (DCs) to respond to pathogens or other danger signals and initiate innate and adaptive immune responses. We are now beginning to appreciate that many of these pathways not only stimulate changes in the expression of genes that control DC immune functions, but also affect metabolic pathways, thereby integrating the cellular requirements of the activation process. In this Review, we focus on this relatively new area of research and attempt to describe an integrated view of DC immunometabolism.

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The Histidine Transporter SLC15A4 Coordinates mTOR-Dependent Inflammatory Responses and Pathogenic Antibody Production

Cited by 131 publications

References 47 publications

Discovery of genes from feces correlated with colorectal cancer progression

Discovery of genes from feces correlated with colorectal cancer progression

The multifaceted biology of plasmacytoid dendritic cells

Dendritic cell metabolism

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