{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNKRF (also known as NRF) is a multifunctional transcriptional regulator that primarily acts as a repressor of NF‐κB–dependent gene expression. Early studies demonstrated that NKRF binds specific negative regulatory elements within target gene promoters to silence basal transcription of inflammatory mediators such as inducible nitric‐oxide synthase, interleukin‐8, and IP‐10—and even modulates transcription elongation in settings such as the HIV‐1 long terminal repeat. This inhibitory function appears central to dampening inflammatory responses in diverse cell types, including airway smooth muscle and immune cells during tuberculosis, thereby preventing excessive cytokine production."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in transcriptional repression, NKRF is predominantly nucleolar and plays key nontranscriptional roles in ribosome biogenesis. It associates with the pre‐ribosomal complex by binding to the transcribed spacer regions of the pre‐rRNA and, in partnership with the RNA helicase DHX15 and the 5′–3′ exonuclease XRN2, facilitates an early rRNA cleavage event and the subsequent turnover of discarded spacer fragments. In addition, NKRF contains RNA binding motifs that mediate its interaction with double‐stranded RNA and help target it to the nucleolus, where under proteotoxic stress it functions as a heat‐shock protein and thermosensor to coordinate nucleolar homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNKRF expression and activity are intricately regulated at multiple levels. Its mRNA harbors an internal ribosome entry segment whose activity is enhanced by specific RNA‐binding factors, such as JKTBP1, which stabilize the transcript and promote cap‐independent translation. In parallel, microRNAs (for example, miR‑802 and miR‑301a‑3p) target the NKRF 3′‑UTR to suppress its expression in pathological settings including obesity‐associated nephropathy and gastric cancer, leading to augmented NF‐κB activation. Furthermore, NKRF is subject to post‐translational modifications and protein–protein interactions—being ubiquitylated by the E3 ubiquitin ligase WWP2 and interacting with cofactors like A1CF—that modulate its inhibitory capacity in tumorigenesis and acute myeloid leukemia. Of note, early cloning and structural analyses revealed that full-length NKRF contains conserved domains (such as the G‑patch and R3H regions) critical for its multifunctional roles."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "19"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xuesheng Feng, Zhong Guo, Mahtab Nourbakhsh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a negative response element in the human inducible nitric-oxide synthase (hiNOS) promoter: The role of NF-kappa B-repressing factor (NRF) in basal repression of the hiNOS gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.212306199"}], "href": "https://doi.org/10.1073/pnas.212306199"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12381793"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12381793"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Ursula Dreikhausen, Kirsten Hiebenthal-Millow, Myriam Bartels, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NF-kappaB-repressing factor inhibits elongation of human immunodeficiency virus type 1 transcription by DRB sensitivity-inducing factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.25.17.7473-7483.2005"}], "href": "https://doi.org/10.1128/MCB.25.17.7473-7483.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16107696"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16107696"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Shu-Chuan Ho, Kang-Yun Lee, Yao-Fei Chan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neutrophil elastase represses IL-8/CXCL8 synthesis in human airway smooth muscle cells through induction of NF-kappa B repressing factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.0803729"}], "href": "https://doi.org/10.4049/jimmunol.0803729"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19542452"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19542452"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Kuo-Hsiung Huang, Chun-Hua Wang, Kang-Yun Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NF-κB repressing factor inhibits chemokine synthesis by peripheral blood mononuclear cells and alveolar macrophages in active pulmonary tuberculosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0077789"}], "href": "https://doi.org/10.1371/journal.pone.0077789"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24223729"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24223729"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Kuo-Hsiung Huang, Chun-Hua Wang, Chien-Huang Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NF-κB repressing factor downregulates basal expression and mycobacterium tuberculosis induced IP-10 and IL-8 synthesis via interference with NF-κB in monocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biomed Sci (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12929-014-0071-5"}], "href": "https://doi.org/10.1186/s12929-014-0071-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25135111"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25135111"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Sascha Rother, Myriam Bartels, Aike Torben Schweda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NF-κB-repressing factor phosphorylation regulates transcription elongation via its interactions with 5'→3' exoribonuclease 2 and negative elongation factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.15-270256"}], "href": "https://doi.org/10.1096/fj.15-270256"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26340924"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26340924"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Ina Niedick, Natali Froese, André Oumard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nucleolar localization and mobility analysis of the NF-kappaB repressing factor NRF."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.01129"}], "href": "https://doi.org/10.1242/jcs.01129"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15226370"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15226370"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Indira Memet, Carmen Doebele, Katherine E Sloan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The G-patch protein NF-κB-repressing factor mediates the recruitment of the exonuclease XRN2 and activation of the RNA helicase DHX15 in human ribosome biogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkx013"}], "href": "https://doi.org/10.1093/nar/gkx013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28115624"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28115624"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Marta Coccia, Antonio Rossi, Anna Riccio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human NF-κB repressing factor acts as a stress-regulated switch for ribosomal RNA processing and nucleolar homeostasis surveillance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1616112114"}], "href": "https://doi.org/10.1073/pnas.1616112114"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28096332"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28096332"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Michael K Studer, Lazar Ivanović, Marco E Weber, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis for DEAH-helicase activation by G-patch proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1913880117"}], "href": "https://doi.org/10.1073/pnas.1913880117"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32179686"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32179686"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Marc René Reboll, André Oumard, Aniko Carla Gazdag, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NRF IRES activity is mediated by RNA binding protein JKTBP1 and a 14-nt RNA element."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "RNA (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1261/rna.545407"}], "href": "https://doi.org/10.1261/rna.545407"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17592041"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17592041"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Deike Johanne Omnus, Sarah Mehrtens, Birgit Ritter, et al. "}, {"type": "b", "children": [{"type": "t", "text": "JKTBP1 is involved in stabilization and IRES-dependent translation of NRF mRNAs by binding to 5' and 3' untranslated regions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2011.01.050"}], "href": "https://doi.org/10.1016/j.jmb.2011.01.050"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21300069"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21300069"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Kang-Yun Lee, Shu-Chuan Ho, Yao-Fei Chan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reduced nuclear factor-κB repressing factor: a link toward systemic inflammation in COPD."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Respir J (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1183/09031936.00146811"}], "href": "https://doi.org/10.1183/09031936.00146811"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22441735"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22441735"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Kseniya Khamina, Alexander Lercher, Michael Caldera, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of host proteins interacting with the lymphocytic choriomeningitis virus L protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Pathog (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.ppat.1006758"}], "href": "https://doi.org/10.1371/journal.ppat.1006758"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29261807"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29261807"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Da Sun, Jia Chen, Wei Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-802 causes nephropathy by suppressing NF-κB-repressing factor in obese mice and human."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.14193"}], "href": "https://doi.org/10.1111/jcmm.14193"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30729676"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30729676"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Xiaodong Xu, Yingjie Xia, Jie Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Upregulation of miRNA‑301a‑3p promotes tumor progression in gastric cancer by suppressing NKRF and activating NF‑κB signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Oncol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijo.2020.5072"}], "href": "https://doi.org/10.3892/ijo.2020.5072"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32468020"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32468020"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Hongjia Wang, Xin Lian, Kexin Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WWP2 binds to NKRF, enhances the NF-κB signaling, and promotes malignant phenotypes of acute myeloid leukemia cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Cell Biol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1139/bcb-2022-0360"}], "href": "https://doi.org/10.1139/bcb-2022-0360"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37921219"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37921219"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Yamin Liu, Jieru Yang, Dunchu Weng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A1CF Binding to the p65 Interaction Site on NKRF Decreased IFN-β Expression and p65 Phosphorylation (Ser536) in Renal Carcinoma Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms25073576"}], "href": "https://doi.org/10.3390/ijms25073576"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38612387"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38612387"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Dai Jianfeng, Jin Feng, Ji Chaoneng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cloning of the correct full length cDNA of NF-kappaB-repressing factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cells (2003)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14744032"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14744032"}]}]}]}