Negative regulator NLRC3: Its potential role and regulatory mechanism in immune response and immune-related diseases

Abstract

NLRC3 is a member of the pattern recognition receptors nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) family, and plays a pivotal regulatory role in modulating the activation of immune cells. In macrophages, NLRC3 inhibits the activation of the NF-κB signaling pathway, the STING/TBK1 signaling pathway, and the formation of the inflammasome. In the context of T cells immune response, NLRC3 prevents the activation of T cells by regulating the function of dendritic cells and directly influencing the function of T cells. Different from other pattern recognition receptors, NLRC3 is more closely associated with regulatory activity than pathogens recognition, it influences the fates of cells, for example, prevents proliferation, promotes apoptosis and inhibits pyroptosis. These cellular functions regulated by NLRC3 are involved in the development processes of a variety of diseases, such as infectious disease, sterile inflammatory diseases, and cancer. However, its characteristics, function and regulatory mechanism in immune response and immune-related diseases have not been addressed fully. In this review, we elaborate the potential roles of NLRC3 from several different levels, include molecular mechanism, cellular functions in the immune-related diseases.

Keywords: NF-κB; NLRC3; NOD-like receptor; PI3K; immune response; immune-related diseases; pyroptosis; sting.

Figure 1

Structure of NLRC3 in different species. (A) From N-terminal to C-terminal, human NLRC3 is composed of CARD domain, NBD domain and LRR domain. (B–D) Three types of structures of fish NLRC3, from N-terminal to C-terminal, the composition and order of the domain are (B) CARD domain, NBD domain and LRR domain (C) FISNA domain, NBD domain, LRR domain and SPRY_PRY_SNTX domain (D) PYD domain, FISNA domain and NBD domain.

Figure 2

The regulatory mechanism of NLRC3. (A) The TRAF6 and IRAK1 activation upon LPS stimulation further activate the NF-κB signaling pathway. NLRC3 prevents the K63-linked polyubiquitination of TRAF6 and promotes the degradation of TRAF6 through proteasome, or NLRC3 promotes the K48-linked polyubiquitination of IRAK1 and promotes the degradation of IRAK1 through proteasome. (B) Upon the Bacteria, Virus infection and c-di-GMF stimulation, the DNA binding to LRR domain of NLRC3 increased the activation of ATPase on the NBD domain of NLRC3, prevented the association of NLRC3 and STING and inhibited the STING/TBK1 signaling pathway. IQGAP1 interacted with NLRC3, promoted NLRC3 to bind with STING and TBK1, and further enhanced the inhibitory effect of NLRC3 on STING/TBK1 signaling pathway. All further attenuates the production of type I interferon (I-IFN), preventing the inflammatory response of macrophages. (C) NLRC3 interacts with ASC and pro-CASP1 through the NBD domain, then prevents the formation of the inflammasome, and makes cells stay away from pyroptosis. (D) NLRC3 interacts with the p85 subunit of PI3K, then inhibits the interaction of p85 submit and catalytic submit p110α, preventing the phosphorylation and activation of the p110α submit, which blocks the transmission of downstream signals, including PI3K-AKT-mTOR and PI3K-AKT-FoxO3a/FoxO1 signaling pathways; P62 interacting with TRAF6 induced the activation of mTOR, NLRC3 prevents the K63-linked polyubiquitination of TRAF6, and negatively regulates the mTOR signaling pathway and prevents cell proliferation. (E) NLRC3 interacts with HSP90 to inhibit HSP90-mediated ubiquitination of P53 and inhibit the degradation of P53 in lysosomes.

Figure 3

Roles of NLRC3 on cell fates. (A) NLRC3 inhibits cell proliferation. NLRC3 interferes the normal function of PI3K or inhibits the activation of mTOR through directly regulating itself and interfering TRAF6, thereby preventing its downstream molecules mTOR, FoxO1 and FoxO3a, and further regulate the cell proliferation. (B) NLRC3 might promote the cell apoptosis. (C) NLRC3 prevents the interaction with ASC and pro-CASP1, further inhibit the formation of inflammasome and cell pyroptosis.

Figure 4

Roles of NLRC3 on macrophage: Upon the infection of gram-negative bacteria, NLRC3 decreases the activation of the NF-κB signal pathway and the release of multiple inflammatory cytokines such as TNF-α and IL-6 by TRAF6-dependent manner. Upon the infection of the virus, NLRC3 prevents the activation of STING/TBK1 signal pathway and the following release of I-IFN through inhibiting STING and TBK1 from functioning normally. Upon the PAMPs stimulation, NLRC3 competitively binding ASC and pro-CASP1 with NLRP3 prevents the formation of inflammasome and pyroptosis.

Figure 5

Roles of NLRC3 on T cells. (A) NLRC3 affects the differentiation direction of naïve T cells. NLRC3 prevents the production and release of IL-6, IL-23 and IL-12 in dendritic cells and naïve T cells, in DCs, NLRC3 executes regulatory roles by affecting P38 signal pathway. IL-12 promotes the differentiation of naïve T cells into Th1 cell, and IL-23, IL-6 promote the differentiation of naïve T cells into Th17 cell. (B, C) The potential several manners of NLRC3 affects the activation, proliferation and differentiation of T cells. (B) Sufficient energy is critical for the activation, proliferation and activation of naïve T cells, NLRC3 regulates the activation, proliferation and differentiation through negatively regulating mitochondrial function and the production of energy in naïve T cells (C) NLRC3 inhibits the activation of both NF-κB and MEK/ERK signal pathways and further inhibit the activation, proliferation and differentiation of T cells.