NLRC5: a newly discovered MHC class I transactivator (CITA)

Abstract

Major histocompatibility complex (MHC) class I and class II are crucial for the function of the human adaptive immune system. An NLR protein, CIITA (MHC class II transactivator), is a master regulator of MHC class II gene expression as well as of some of the genes involved in MHC class II antigen presentation. It has recently been discovered that another member of the NLR protein family, NLRC5, transcriptionally activates MHC class I genes, and thus acts as "CITA" (MHC class I transactivator), a counterpart to CIITA. In addition to MHC class I genes, NLRC5 can induce the expression of β2M, TAP1 and LMP2, essential components of MHC class I antigen presentation. These findings indicate that NLRC5 and CIITA are transcriptional regulators that orchestrate the concerted expression of critical components in the MHC class I and MHC class II pathways, respectively.

Figure 1. NLRC5 has a typical tripartite domain structure characteristic of the NLR protein family

The schematic structures of CIITA (B-CIITA), the DC-specific isoform of CIITA (DC-CIITA), and NLRC5 are shown. X: variable N-terminal effector domain. NBD: nucleotide binding domain. LRR: leucine-rich repeats. AD: acidic domain or activation domain. P/S/T domain: proline-serine-threonine-rich domain. NLS: nuclear localization signal. CARD: caspase recruitment domain.

Figure 2. Model of transcriptional regulation of MHC class I and class II genes by the “CITA” and the CIITA enhanceosome, respectively

A) MHC class II gene regulation by CIITA: IFN-γ stimulation activates STAT1, which induces the expression of CIITA, directly and/or indirectly via the transcription factor IRF-1. CIITA associates with the DNA binding protein complexes RFX, CREB/ATF1 and NF-Y to form the CIITA enhanceosome complex on the conserved WXY motif in the MHC class II gene promoters to transactivate MHC class II genes. B) MHC class I gene regulation by CITA or NLRC5: IFN-γ stimulation induces NLRC5 expression via direct binding of activated STAT1 homodimers to the GAS sites in the NLRC5 promoter. Subsequently, NLRC5 may generate a “CITA” enhanceosome on the MHC class I promoter together with transcription factors bound to the WXY motif. The promoters of most MHC class I genes also contain binding sites for NF-κB (Enhancer A) and IRF-1 (ISRE), which may further modulate NLRC5-mediated MHC class I gene expression.