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      A heterozygous N-terminal truncation mutation of NFKBIA results in an impaired NF-κB dependent inflammatory response


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          Germline heterozygous gain-of-function (GOF) mutation of NFKBIA, encoding IκBα, would affect the activation of NF-κB pathway and cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Here we reported a Chinese patient with a heterozygous N-terminal truncation mutation of NFKBIA/IκBα. She presented recurrent fever, infectious pneumonia and chronic diarrhea with EDA-ID. Impaired NF-κB translocation and IL1R and TLR4 pathway activation were revealed in this patient. The findings suggested that the truncation mutation of IκBα caused medium impaired of activation of NF-κB but the early death. Furthermore, we reviewed all the reported patients with NFKBIA mutation to learn more about this disease.

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          Missing pieces in the NF-kappaB puzzle.

          The regulation of the transcription factor NF-kappaB activity occurs at several levels including controlled cytoplasmic-nuclear shuttling and modulation of its transcriptional activity. A critical component in NF-kappaB regulation is the IkappaB kinase (IKK) complex. This review is focused on recent progress as well as unanswered questions regarding the regulation and function of NF-kappaB and IKK.
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            Regulation and function of NF-kappaB transcription factors in the immune system.

            The mammalian Rel/NF-kappaB family of transcription factors, including RelA, c-Rel, RelB, NF-kappaB1 (p50 and its precursor p105), and NF-kappaB2 (p52 and its precursor p100), plays a central role in the immune system by regulating several processes ranging from the development and survival of lymphocytes and lymphoid organs to the control of immune responses and malignant transformation. The five members of the NF-kappaB family are normally kept inactive in the cytoplasm by interaction with inhibitors called IkappaBs or the unprocessed forms of NF-kappaB1 and NF-kappaB2. A wide variety of signals emanating from antigen receptors, pattern-recognition receptors, receptors for the members of TNF and IL-1 cytokine families, and others induce differential activation of NF-kappaB heterodimers. Although work over the past two decades has shed significant light on the regulation of NF-kappaB transcription factors and their functions, much progress has been made in the past two years revealing new insights into the regulation and functions of NF-kappaB. This recent progress is covered in this review.
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              Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity.

              NF-kappaB (nuclear factor-kappaB) is a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-kappaB is found in essentially all cell types and is involved in activation of an exceptionally large number of genes in response to infections, inflammation, and other stressful situations requiring rapid reprogramming of gene expression. NF-kappaB is normally sequestered in the cytoplasm of nonstimulated cells and consequently must be translocated into the nucleus to function. The subcellular location of NF-kappaB is controlled by a family of inhibitory proteins, IkappaBs, which bind NF-kappaB and mask its nuclear localization signal, thereby preventing nuclear uptake. Exposure of cells to a variety of extracellular stimuli leads to the rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of IkappaB, which frees NF-kappaB to translocate to the nucleus where it regulates gene transcription. NF-kappaB activation represents a paradigm for controlling the function of a regulatory protein via ubiquitination-dependent proteolysis, as an integral part of a phosphorylationbased signaling cascade. Recently, considerable progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1. The multisubunit IkappaB kinase (IKK) responsible for inducible IkappaB phosphorylation is the point of convergence for most NF-kappaB-activating stimuli. IKK contains two catalytic subunits, IKKalpha and IKKbeta, both of which are able to correctly phosphorylate IkappaB. Gene knockout studies have shed light on the very different physiological functions of IKKalpha and IKKbeta. After phosphorylation, the IKK phosphoacceptor sites on IkappaB serve as an essential part of a specific recognition site for E3RS(IkappaB/beta-TrCP), an SCF-type E3 ubiquitin ligase, thereby explaining how IKK controls IkappaB ubiquitination and degradation. A variety of other signaling events, including phosphorylation of NF-kappaB, hyperphosphorylation of IKK, induction of IkappaB synthesis, and the processing of NF-kappaB precursors, provide additional mechanisms that modulate the level and duration of NF-kappaB activity.

                Author and article information

                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                03 April 2021
                January 2022
                03 April 2021
                : 9
                : 1
                : 176-186
                [a ]Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing 400014, PR China
                [b ]Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400014 PR China
                [c ]Pediatric Research Institute, Chongqing, 400014 PR China
                [d ]Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, PR China
                [e ]National Clinical Research Center for Child Health and Disorders, Chongqing, 400014 PR China
                [f ]China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing 400014, PR China
                [g ]Children's Hospital of Chongqing Medical University, Chongqing 400014, PR China
                Author notes
                [∗∗ ]Corresponding author. Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, PR China. maohwei@ 123456qq.com
                []Corresponding author. Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, PR China. zhaoxd530@ 123456aliyun.com
                © 2021 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 14 December 2020
                : 21 February 2021
                : 24 March 2021
                Full Length Article

                ad-eda-id,hsct,iκbα,nf-κb activation,nfkbia
                ad-eda-id, hsct, iκbα, nf-κb activation, nfkbia


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