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NLR Family Member NLRC5 Is a Transcriptional Regulator of MHC Class I Genes

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NLR Family Member NLRC5 Is a Transcriptional Regulator of MHC Class I Genes NLR family member NLRC5 is a transcriptional regulator of MHC class I genes Torsten B. Meissnera,b, Amy Lia, Amlan Biswasa,b, Kyoung-Hee Leea,b, Yuen-Joyce Liua, Erkan Bayira, Dimitrios Iliopoulosc, Peter J. van den Elsend,e, and Koichi S. Kobayashia,b,1 aDepartment of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115; bDepartment of Pathology, Harvard Medical School, Boston, MA 02115; cDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; dDepartment of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; and eDepartment of Pathology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands Communicated by Jack Strominger, Harvard University, Cambridge, MA, June 18, 2010 (received for review June 1, 2010) MHC class I plays a critical role in the immune defense against viruses plexes (7, 8). These transcription factors include the X-box binding and tumors by presenting antigens to CD8 T cells. An NLR protein, trimeric RFX protein complex (composed of RFX5, RFXAP, and class II transactivator (CIITA), is a key regulator of MHC class II gene RFXANK), the ×2-box binding cAMP response element binding expression that associates and cooperates with transcription factors protein/activating transcription factor (CREB/ATF), and the Y-box in the MHC class II promoter. Although CIITA also transactivates MHC binding nuclear factor-Y protein (composed of NF-YA, NF-YB, class I gene promoters, loss of CIITA in humans and mice results in the and NF-YC) (9). Together, they form a macromolecular nucleo- severe reduction of only MHC class II expression, suggesting that protein complex called the MHC enhanceosome (10). additional mechanisms regulate the expression of MHC class I. Here, Class II transactivator (CIITA), a member of the NLR or nu- we identify another member of the NLR protein family, NLRC5, as cleotide binding domain (NBD) leucine-rich repeat (LRR) family a transcriptional regulator of MHC class I genes. Similar to CIITA, of proteins (11, 12), regulates the transcription of MHC class II by NLRC5 is an IFN-γ–inducible nuclear protein, and the expression of associating with the MHC enhanceosome (10, 13). The expression NLRC5 resulted in enhanced MHC class I expression in lymphoid as of CIITA is induced in B cells and dendritic cells as a function of well as epithelial cell lines. Using chromatin immunoprecipitation developmental stage and is inducible by IFN-γ in most cell types and reporter gene assays, we show that NLRC5 associates with and (14–16). There are 22 NLR proteins in humans, which share three IMMUNOLOGY activates the promoters of MHC class I genes. Furthermore, we show characteristic functional domains: an N-terminal protein–protein γ– that the IFN- induced up-regulation of MHC class I requires NLRC5, interaction domain such as a caspase recruitment domain (CARD) NLRC5 fi because knockdown of speci cally impaired the expression of or a PYRIN domain, a centrally located NBD (or NACHT, NAIP, MHC class I. In addition to MHC class I genes, NLRC5 also induced the β CIITA, HET-E and TP1 domain), and C-terminal LRRs (11, 12). expression of 2-microglobulin, transporter associated with antigen Aside from CIITA, NLR proteins are localized in the cytoplasm processing, and large multifunctional protease, which are essential and contribute to the innate immune response by recognizing mi- for MHC class I antigen presentation. Our results suggest that NLRC5 crobial products and exogenous danger signals, leading to inflam- is a transcriptional regulator, orchestrating the concerted expression mation and/or cell death (11, 12). of critical components in the MHC class I pathway. Previous studies have shown that, although to a lesser extent, CIITA also has a role in the transactivation of MHC class I genes antigen presentation | class II transactivator | IFN-γ (6–9, 17). However, the expression of CIITA is generally restricted to lymphocytes and professional antigen-presenting cells and thus, HC class I and class II play essential roles in the activation of is unlikely to account for the ubiquitous expression of MHC class I Madaptive immune responses by presenting antigens to T lym- (6, 18). Furthermore, although mutations of the CIITA gene can phocytes. MHC class I molecules are composed of MHC-encoded cause bare lymphocyte syndrome (BLS), an immunodeficiency β β heavy chains and the invariant subunit 2-microglobulin ( 2M) (1). characterized by the lack of MHC class II expression, a subgroup of Humans have three classical MHC class Ia molecules (HLA-A, BLS patients that lack CIITA retains the expression of MHC class I HLA-B,andHLA-C),whicharevitaltothedetectionandelimina- but not MHC class II (19, 20). Similarly, in mice deficient for tion of viruses, cancerous cells, and transplanted cells. In addition, CIITA, both constitutive and IFN-γ–induced expression of MHC there are three nonclassical MHC class Ib molecules (HLA-E, HLA- class I molecules is intact (21–23). These findings indicate that, in F, and HLA-G), which have immune regulatory functions (2, 3). addition to CIITA, other molecules or mechanisms are involved in Antigen-derived peptides are presented by MHC class I–β2M the regulation of MHC class I expression. complexes at the cell surface to CD8 T cells carrying an antigen- Here, we show that another NLR protein, NLRC5 (NLR family, specific T cell receptor. Peptides are mostly produced from the CARD domain containing 5/NOD27/CLR16.1), regulates the ex- degradation of cytoplasmic proteins by a specialized proteasome or pression of MHC class I. Similar to CIITA, NLRC5 is highly in- immunoproteasome, which is optimized to generate MHC class I ducible by IFN-γ and can translocate into the nucleus. We show peptides and contains several IFN-γ–inducible subunits, such as large that NLRC5 activates the promoters of MHC class I genes and multifunctional protease 2 (LMP2) and LMP7 (4). Peptide loading onto MHC class I is carried out by the peptide-loading complex (PLC), which includes the MHC class I heavy chain, β2M, tapasin, Author contributions: T.B.M., A.L., and K.S.K. designed research; T.B.M., A.L., A.B., K.-H.L., endoplasmic reticulum (ER)p57, calreticulin, and transporter asso- Y.-J.L., E.B., and D.I. performed research; P.J.v.d.E. contributed new reagents/analytic ciated with antigen processing 1 (TAP1)/TAP2, a transporter that tools; T.B.M., A.L., A.B., K.-H.L., Y.-J.L., E.B., D.I., and K.S.K. analyzed data; and T.B.M., A.L., and K.S.K. wrote the paper. translocates peptides from the cytoplasm into the ER (4, 5). fl Unlike MHC class II, which is found mainly in antigen-pre- The authors declare no con ict of interest. Data deposition: The data reported in this paper have been deposited in the Gene Ex- senting cells, MHC class Ia is ubiquitously expressed in almost all pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE22064). nucleated cells (1, 6). Both MHC class I and class II genes are highly 1 γ To whom correspondence should be addressed. E-mail: [email protected]. inducible by IFN- stimulation and share similar cis-regulatory edu. elements in their promoters, termed W/S, X1, X2, and Y-box This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. motifs, which also associate with similar transcription factor com- 1073/pnas.1008684107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1008684107 PNAS Early Edition | 1of6 Downloaded by guest on September 26, 2021 induces the transcription of MHC class I as well as related genes obtained using the murine Nlrc5, which can also be trapped in the involved in MHC class I antigen presentation, suggesting that nucleus on LMB treatment (Fig. S2). NLRC5 is a critical regulator of MHC class I-mediated immu- Given the predicted size of the NLRC5 fusion protein (∼230 ne responses. kDa), passive diffusion through the nuclear pore is not possible. Active transport, however, requires the presence of an NLS that is Results recognized by nuclear import receptors (27). To identify the NLS NLRC5 Contains a Nuclear Localization Signal and Shuttles Between of NLRC5, we performed deletion mutant analysis. As depicted in the Cytosol and Nucleus. To study the function of NLRC5, we in- Fig. 1C, we expressed the deletion mutants of NLRC5 as GFP vestigated its cellular distribution using a GFP fusion protein. To fusion proteins. Although all fusion constructs containing an intact our surprise, NLRC5 was found not only in the cytosol but also in N-terminal CARD (WT, CARD, and ΔLRR) were found in the the nucleus (Fig. 1A Upper). We checked the stability of the fusion nucleus, deletion of the CARD (ΔCARD and LRR) resulted in protein by Western blot analysis, confirming that its nuclear lo- a strictly cytosolic localization (Fig. 1D). Similar to free GFP, the calization was not caused by a smaller, GFP-containing cleavage NACHT domain fusion protein was found in both the nucleus and product (Fig. S1A). It has been shown that CIITA, which also cytosol, presumably because of passive diffusion as a result of its displays a heterogeneous steady-state distribution, shuttles be- smaller size. These results suggested that an NLS may be located in tween the nucleus and cytosol as a result of nuclear localization the N-terminal CARD. Indeed, sequence analysis of NLRC5 signal (NLS)-mediated nuclear import and exportin-1 (CRM1)- revealed a putative bipartite NLS at the transition between the dependent nuclear export (24–26). Similar to CIITA, which is CARD and the NBD (Fig. 1E) (25, 26). As predicted, mutation of a closely related member of the NLR protein family (Fig.
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