NLRC5 Functions beyond MHC I Regulation-What Do We Know So Far?

Abstract

NLRC5 is a member of the NLR family that acts as a transcriptional activator of MHC class I genes. In line with the function of several related NLR proteins in innate immune responses, there is, however, also ample evidence that NLRC5 contributes to innate and adaptive immune responses beyond the regulation of MHC class I genes. In human and murine cells, for example, NLRC5 was proposed to contribute to inflammatory and type I interferon responses. The role of NLRC5 in these and other cellular processes is hitherto still not well understood and blurred by discrepancies in the reported data. Here, we provide a detailed and critical discussion of the available experimental data on the emerging biological functions of NLRC5 in innate immune responses in men and mice. Better awareness of the multiple roles of NLRC5 will help to define its overall contribution to immune responses and cancer.

Keywords: IFN; MHC; NF-κB; NLR; inflammasome; innate immunity.

Figure 1

Schematic representation of the human NLRC5 protein structure and domain organization. uCARD, untypical caspase activation and recruitment domain (CARD); this domain shows only low sequence similarities to canonical CARD domains. A nuclear localization signal is located in this region. NACHT domain, involved in the nucleotide bindings and presumable important for oligomerization and activation of NLRC5. WA and WB are Walker A and Walker B motifs, respectively. The WA motif is responsible for nucleotide triphosphate binding; WB motif is responsible for nucleotide triphosphate hydrolysis. WH, winged helix domain. SH, superhelical domain, contains eight α-helices, function unknown. LRR, leucine-rich repeat, protein–protein interaction domain, responsible for ligand binding in other pattern-recognition receptors.

Figure 2

Schematic representation of the proposed cellular functions of cellular NLRC5. (A) Several studies suggest a contribution of NLRC5 to the nuclear factor kappa B (NF-κB) pathway. This might involve specific ubiquitination of NLRC5. A direct interaction between the IKKα/β and NLRC5 resulting in IKKα/β, which is unable to bind to NEMO (IKKγ) as well as reduced autophosphorylation and kinase activity was reported. Following lipopolysaccharide treatment, the TNF receptor-associated factors 2/6 (TRAF2/6) mediate NLRC5 ubiquitination. This leads to the degradation of NLRC5 that consequently frees IKKα/β complex and activates NF-κB pathway. (B) Possible role of NLRC5 in controlling inflammasome activation. The molecular mechanisms how this is achieved remains elusive. NLRC5 might affect priming by the regulation of NF-κB responses or might directly interfere with inflammasome activation. However, available data suggest that NLRC5 is more likely involved in the complex forming step of the inflammasome activation. (C) In antiviral responses, some studies suggest that NLRC5 interacts with retinoic acid-inducible gene I (RIG-I) and MAVS and might be able to enhance type I interferon responses. However, also contradicting data, suggesting a role of NLRC5 I inhibiting type I interferon responses has been presented. Several studies showed that in the absence of NLRC5, the IFNβ response is significantly weaker compared to the level observed when NLRC5 interacts with RIG-I and MAVS. (D) Finally, recent works suggest that NLRC5 can be linked to tumorigeneses via multiple pathways, such as β-catenin, TGF-β, and Akt, thereby resulting in changed cell proliferation and extracellular matrix deposition. However, these functions await validation at present. It should be mentioned that most of the depicted functions await further clarification (see main text for discussion).