NLRC5

Official Full Name

NLR family CARD domain containing 5

Organism

Homo sapiens

GeneID

84166

Background

This gene encodes a member of the caspase recruitment domain-containing NLR family. This gene plays a role in cytokine response and antiviral immunity through its inhibition of NF-kappa-B activation and negative regulation of type I interferon signaling pathways. [provided by RefSeq, Oct 2011]

Synonyms

NOD4; NOD27; CLR16.1;

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Detailed Information

NLRC5 is also known as NOD27 or ELJ21709 or CLR 16.1. NLRC5 has been shown to be an important regulator of nuclear factor kappa B, type I interferons, inflammasome signaling pathways, and MHC-I gene expression, playing a pivotal role in innate and adaptive immune responses.

The expression of NLRC5 itself is regulated by the NF-κB signal pathway, thus forming a negative feedback loop. When lipopolysaccharide stimulates the presence of certain NLRC5 cells, the NFRC5 signaling pathway is activated and the NLRC5 gene and its protein are highly expressed. At this time, due to the high expression of NLRC5 and its relative molecular mass, it can physically block the binding of NEMO to IKKα and IKKβ, while NLRC5 itself interacts with the activated forms of IKKα and IKKβ, thereby preventing IKKα and IKKβ from going. Phosphorylation of IκBα and IKK complexes achieves the goal of inhibiting the NF-κB signaling pathway. Inactive NF-κB remains in the cytoplasm and is adjacent to IκB family members in the inhibitory protein family, making IκB family members upstream of the signal pathway. Due to the interaction of NLRC5 with IKKα and IKKβ, the inhibitory protein IκB could not be phosphorylated, which ultimately blocked the activation of NF-κB signal pathway.

Nlrc5 Figure1. Schematic representation of the proposed cellular functions of cellular NLRC5. (Szilvia, B., et al. 2017)

Effect of NLRC5 on MHC-I Gene

MHC-I plays a key role in the anti-viral and anti-tumor effects of antigen presentation to CD8+ T cells. Strict control of MHC-I gene expression is critical for CD8+ T cell activation and adaptive immune response. In living organisms, NLRC5 is a key regulator of host cell defense against intracellular pathogens and is also a transcriptional regulator of the MHC-I gene. NLRC5 combines the neighbors of the MHC-I gene and reactivates these activators. The NLRC5-mediated MHC-I gene induction requires the W/S, X1, and X2 cis-regulator components. In NLRC5-deficient mice, the MHC-I gene is apparently deficient, and its concomitant cannot activate the CD8+ T cell response. Furthermore, the mice are more susceptible to pathogens. Knocking out NLRC5 in different human cell lines and major dermal fibroblasts also resulted in a decrease in MHC-I gene expression. Introduction of NLRC5 in cells with very low MHC-I gene expression enhances the expression level of this gene.

The Role of NLRC5 in Immunity

Overexpression of NLRC5 can cause up-regulation of IFN expression. NLRC5 has an independent role in the cytomegalovirus-induced immune response, indicating that NLRC5 may be involved in the anti-viral response. In addition, NLRC5 may affect NOD2-mediated antiviral responses. It has been demonstrated in human monocyte experiments that RNA interference-mediated knockout of NLRC5 virtually eliminates the response of caspase-1, IL-1β and IL-18 to bacterial infections, PAMPs, and risk-related molecular patterns. NLRC5 forms an inflammasome activity with proproteinase-1 and pre-IL-1β inflammasome adapter ASC. This behavior also requires NLRP3 cooperation, suggesting that NLRC5 interacts with NLRP3 to activate the inflammatory body and cause an immune response.

However, studies have also shown that overexpression of NLRC5 in HEK293T cells is likely to completely inhibit NF-κB, AP-1, and immune responses relying on IFN-I signaling pathways through transcriptional repression. Knocking out the NLRC5 gene in RAW264.7 murine macrophages induced an effective up-regulation of IFN-γ and lipopolysaccharide pro-inflammatory responses, including increased tumor necrosis factor, IL-6, IL-1β secretion and increased CD40 expression on the cell surface. This negative regulation of immune inflammatory response suggests that NLRC5 is likely to be a target for the regulation of immune responses to inflammatory diseases, autoimmune diseases or sepsis.

References:

Szilvia, B. , Kovács Elek Gerg?, Felix, H. , & Kufer, T. A. . (2017). Nlrc5 functions beyond mhc i regulation—what do we know so far?. Frontiers in Immunology, 8.
Vijayan, S. , Sidiq, T. , Yousuf, S. , Van, d. E. P. J. , & Kobayashi, K. S. . (2019). Class i transactivator, nlrc5: a central player in the mhc class i pathway and cancer immune surveillance. Immunogenetics.

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