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Maturation, Barrier Function, Aging, and Breakdown of the Blood–Brain Barrier
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Elizabeth de Lange, Ágnes Bajza, Péter Imre, Attila Csorba, László Dénes, Franciska Erdő
Although disruption of AJs can result in increased BBB permeability, TJs are primarily responsible for restricting paracellular permeability at the BBB (Hawkins and Davis 2005, Zlokovic 2008). TJs form the primary physical barrier component of the BBB and function to greatly restrict paracellular entry of various endogenous and exogenous substances that can potentially be neurotoxic. TJs are dynamic complexes of multiple protein constituents including junctional adhesion molecules (JAMs), occludin, claudins (i.e., claudin-1, -3, and -5), and membrane-associated guanylate kinase (MAGUK)-like proteins (i.e., ZO-1, -2, and -3) (Hawkins and Davis 2005) (Figure 15.3).
Genetics
Published in M. Alan Menter, Caitriona Ryan, Psoriasis, 2017
CARD14 is represented by several isoforms.8 Full-length CARD14 (CARD14fl, also known as CARD14 isoform 1) encodes both an N-terminal CARD domain necessary for activation of NF-κB and a C-terminal tripartite membrane-associated guanylate kinase (MAGUK) domain (PDZ/SH3/GUK) that is involved in relaying external signals to the inside of the cell. This is the only isoform that harbors the p.R820W polymorphism. A shorter isoform, CARD14sh, encodes the CARD domain but not the MAGUK domain. CARD14sh is the most abundant isoform in all tissues where it is expressed, including skin. Another isoform, CARD14cl, lacks the CARD and the tripartite domain and is unable to activate NF-κB.8,78CARD14cl has a very restricted pattern of expression, which is confined to the epidermis, thymus, and placenta8 and possibly lung and cervix.78 CARD14-induced activation of NF-κB is dependent on TRAF278 and might also require TRAF3 or TRAF6. Moreover, CARD14 may fit into other known Ps associated pathways such as IL-17/Act1. Figure 4.3 provides possible signaling pathways involving CARD14 that are operating in the keratinocyte and endothelial cell in Ps. Genes in regions identified through GWAs are highlighted.
COP1 facilitates the proliferation, invasion, and migration of glioma cells by ubiquitination of DLG3 protein
Published in Neurological Research, 2023
Tumor growth involves the reorganization of cell polarity and the abnormal alteration in the expression of scaffolding proteins related to polarity complexes [10]. Discs large homolog 3 (DLG3) scaffolding protein, a member of the membrane-associated guanylate kinase family, is abundantly expressed in the brain and participates in the modulation of synaptic functions [11]. Downregulation of DLG3 contributes to the initiation and progression of human malignancies, such as oral squamous cell carcinoma [12], colon cancer [13], and pancreatic cancer [14]. DLG3 expression is aberrantly reduced in glioblastoma, and DLG3 overexpression triggers glioblastoma cell apoptosis but depresses proliferation and migration [15]. The functions of DLG3 regulating apical-basal polarity and tight junction consolidation require the involvement of E3 ubiquitin ligases [16]. However, whether E3 ubiquitin ligase COP1 participates in glioma progression by manipulating the ubiquitination of DLG3 remains unknown. Herein, this study set out to determine the molecular mechanism of COP1-mediated ubiquitination in glioma cell proliferation, invasion, and migration, hoping to confer a novel theoretical basis for COP1 as a molecular target in the treatment of glioma.
Genome-Wide Association Study of Ocular Sarcoidosis Confirms HLA Associations and Implicates Barrier Function and Autoimmunity in African Americans
Published in Ocular Immunology and Inflammation, 2021
Lori Garman, Nathan Pezant, Ambra Pastori, Kathryn A. Savoy, Chuang Li, Albert M. Levin, Michael C. Iannuzzi, Benjamin A. Rybicki, Indra Adrianto, Courtney G. Montgomery
We further identified a compelling candidate gene that encodes for the scaffolding protein MAGI1 (membrane-associated guanylate kinase WW and PDZ domain-containing protein 1). MAGI1 is integral to the multiprotein complexes of tight junctions and expressed in many tissues, including the lens and retina.31,32 Together with other proteins, MAGI1 ensures that the epithelial barrier in the eyes and other organs is highly selective in its permeability.33,34 SNPs in MAGI1 have been associated with inflammatory disorders in which barrier integrity is compromised, including spontaneous glomerulosclerosis,34 celiac disease,35 medically refractory ulcerative colitis,36 and the stricturing Crohn’s disease phenotype.37 In a rodent model of experimental autoimmune uveitis mediated by peptide-specific CD4 + T cells, MAGI1 was upregulated in T cells capable of inducing remitting disease as compared to those that induce monophasic disease.38MAGI1 at OS-associated SNP rs4437178 is bound by the transcription factor MZF-1, which has known immune-associated targets such as NOS1 (IPA). MAGI1 is also thought to regulate type I interferon, and contains TFBSs for immune regulating transcription factors BLIMP-1, STAT1, and NFkB.39
Current techniques to accurately measure anti-retinal autoantibodies
Published in Expert Review of Ophthalmology, 2020
Phage immunoprecipitation sequencing (PhIP-Seq) is a new technique for autoantigen discovery that is based on a synthetic representation of a complete human peptidome [44,45]. This method has been used to identify novel autoantigens in neurologic paraneoplastic disorders, multiple sclerosis, and rheumatoid arthritis. PhIP-Seq was also used for an identification of novel autoantigens expressed in the retina in AR patients (RTN3, PRPF6, TRPC6, and B3GNT8), but not in healthy controls [46]. A human proteome (HuProt) microarray, representing >80% of all protein-coding genes, was screened with serum from a patient with suspected CAR [25]. This method identified aryl hydrocarbon receptor-interacting protein-like (AIPL)-1, a protein specifically restricted to the retina and the pineal gland. The array also identified lipocalin 8, membrane-associated guanylate kinase WW, PDZ-containing domain 1, and doublecortin domain-containing 2 [25]. Those procedures are limited to the analysis of linear epitopes and the expression of some epitopes in bacteria is difficult.