CITA/NLRC5: A critical transcriptional regulator of MHC class I gene expression

Downs, Isaac; Vijayan, Saptha; Sidiq, Tabasum; Kobayashi, Koichi S.

doi:10.1002/biof.1285

Cited by 45 publications

(37 citation statements)

References 69 publications

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“…In the immune system, NLRC5 and CIITA could act as trans‐activators of MHC I genes that cooperated with other transcription factors to form an enhanceosome on the promoter of MHC I genes (Neerincx et al 2012; Downs et al ). In contrast to the restricted expression pattern of CIITA, NLRC5 was constitutively expressed in various tissues.…”

Section: Discussionmentioning

confidence: 99%

Neuronal NLRC5 regulates MHC class I expression in Neuro‐2a cells and also during hippocampal development

Shen

Cui

et al. 2019

Journal of Neurochemistry

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Major histocompatibility Complex class I (MHC I) molecules are ubiquitously expressed, being found in most nucleated cells, where they are central mediators of both the adaptive and innate immune responses. Recent studies have shown that MHC I are also expressed in the developing brain where they participate in synapse elimination and plasticity. Up‐regulation of MHC I within the developing brain has been reported, however, the mechanism(s) regulating this developmental up‐regulation of neuronal MHC I remains unknown. Here, we show NLR family CARD domain containing 5 (NLRC5), a newly identified member of the NLR family, is widely expressed in hippocampal neurons, and the expression pattern of NLRC5 coincides with increased MHC I mRNA in the developing hippocampus. Using a luciferase assay in Neuro‐2a cells we demonstrate that NLRC5 can induce the activation of MHC I and this induction requires the W/S‐X‐Y motif. Further studies show that transcription factors regulatory factor X (RFX) and CREB1, which bind to X1 and X2 box, are crucial for NLRC5‐mediated induction. Moreover immunoprecipitation experiments reveal that NLRC5 interacts with RFX subunits RFX5 and RFXANK. Knockout of Nlrc5 dramatically impairs basal expression of MHC I in mouse hippocampus. Taken together, our findings identify NLRC5 as a key regulator of MHC I up‐regulation in the developing hippocampus and suggest an important role for NLRC5 in neurons. Cover Image for this issue: doi: .

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Section: Discussionmentioning

confidence: 99%

Neuronal NLRC5 regulates MHC class I expression in Neuro‐2a cells and also during hippocampal development

Shen

Cui

et al. 2019

Journal of Neurochemistry

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“…The greatest increase in gene expression was seen in NLRC5 (NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5), an IFNγ-inducible transcriptional coactivator of MHC class I gene expression also known as CITA (MHC class I transactivator) 36 . NLRC5 is the master regulator of MHC class I gene expression and activates most of the key components of the MHC class I antigen presentation pathway 37 . In line with this, non-classical MHC class I HLA-F was in the top 10 upregulated genes in this study, although with a FDR > 0.07.…”

Section: Discussionmentioning

confidence: 99%

Plasmacytoid dendritic cells appear inactive during sub-microscopic Plasmodium falciparum blood-stage infection, yet retain their ability to respond to TLR stimulation

Loughland

Minigo

Sarovich

et al. 2017

Sci Rep

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Plasmacytoid dendritic cells (pDC) are activators of innate and adaptive immune responses that express HLA-DR, toll-like receptor (TLR) 7, TLR9 and produce type I interferons. The role of human pDC in malaria remains poorly characterised. pDC activation and cytokine production were assessed in 59 malaria-naive volunteers during experimental infection with 150 or 1,800 P. falciparum-parasitized red blood cells. Using RNA sequencing, longitudinal changes in pDC gene expression were examined in five adults before and at peak-infection. pDC responsiveness to TLR7 and TLR9 stimulation was assessed in-vitro. Circulating pDC remained transcriptionally stable with gene expression altered for 8 genes (FDR < 0.07). There was no upregulation of co-stimulatory molecules CD86, CD80, CD40, and reduced surface expression of HLA-DR and CD123 (IL-3R-α). pDC loss from the circulation was associated with active caspase-3, suggesting pDC apoptosis during primary infection. pDC remained responsive to TLR stimulation, producing IFN-α and upregulating HLA-DR, CD86, CD123 at peak-infection. In clinical malaria, pDC retained HLA-DR but reduced CD123 expression compared to convalescence. These data demonstrate pDC retain function during a first blood-stage P. falciparum exposure despite sub-microscopic parasitaemia downregulating HLA-DR. The lack of evident pDC activation in both early infection and malaria suggests little response of circulating pDC to infection.

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“…Major histocompatibility complex (MHC) class I molecules provide a window for the immune system [24,25]. The proteolytic generation of peptides is the key point of the immune surveillance system, which considers proteins that are produced from longer gene products [26].…”

Section: Discussionmentioning

confidence: 99%

Adenovirus Vector Harboring the HBcAg and Tripeptidyl Peptidase II Genes Induces Potent Cellular Immune Responses In Vivo

Tan¹,

Ma²,

Hu³

et al. 2017

Cell Physiol Biochem

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Background: Chronic hepatitis B virus (HBV) infection is associated with a weak but specific cellular immune response of the host to HBV. Tripeptidyl peptidaseⅡ (TPPⅡ), an intracellular macromolecule and proteolytic enzyme, plays an important complementary and compensatory role for the proteasome during viral protein degradation and major histocompatibility complex class I antigen presentation by inducing a specific cellular immune response in vivo. Based on a previous study, we aimed to explore the role of MHC class I antigen presentation in vivo and the mechanisms that may be involved. Methods: In this study, recombinant adenoviral vectors harboring the hepatitis B core antigen (HBcAg) and the TPPII gene were constructed (Adv-HBcAg and Adv-HBcAg-TPPII), and H-2Kd HBV-transgenic BALB/c mice and HLA-A2 C57BL/6 mice were immunized with these vectors, respectively. We evaluated the specific immune responses induced by Adv-HBcAg-TPPII in the HBV transgenic BALB/c mice and HLA-A2 C57BL/6 mice as well as the anti-viral ability of HBV transgenic mice, and we explored the underlying mechanisms. Results: We found that immunization with Adv-HBcAg-TPPII induced the secretion of the cytokines interleukin-2 (IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) as well as the activities of IFN-γ-secreting CD8+ T cells and CD4+ T cells. In addition, HBcAg-specific CTL activity in C57/BL mice and HBV transgenic animals was significantly enhanced in the Adv-HBcAg-TPPII group. Furthermore, Adv-HBcAg-TPPII decreased the hepatitis B surface antigen (HBsAg) and HBV DNA levels and the amount of HBsAg and HBcAg in liver tissues. Moreover, Adv-HBcAg-TPPII enhanced the expression of T-box transcription factor (T-bet) and downregulated GATA-binding protein 3 (GATA-3) while increasing the expression levels of JAK2, STAT1, STAT4 and Tyk2. Conclusions: These results suggested that the JAK/STAT signaling pathway participates in the CTL response that is mediated by the adenoviral vector encoding TPPII. Adv-HBcAg-TPPII could therefore break immune tolerance and stimulate HBV-specific cytotoxic T lymphocyte activity and could have a good therapeutic effect in transgenic mice.

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CITA/NLRC5: A critical transcriptional regulator of MHC class I gene expression

Cited by 45 publications

References 69 publications

Neuronal NLRC5 regulates MHC class I expression in Neuro‐2a cells and also during hippocampal development

Neuronal NLRC5 regulates MHC class I expression in Neuro‐2a cells and also during hippocampal development

Plasmacytoid dendritic cells appear inactive during sub-microscopic Plasmodium falciparum blood-stage infection, yet retain their ability to respond to TLR stimulation

Adenovirus Vector Harboring the HBcAg and Tripeptidyl Peptidase II Genes Induces Potent Cellular Immune Responses In Vivo

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