33 research outputs found
K+ regulates relocation of Pellino-2 to the site of NLRP3 inflammasome activation in macrophages
Pellino proteins are E3 ubiquitin ligases involved in the innate immune system. Recently, Pellino-2 was reported to modulate the activation of the mouse Nlrp3 inflammasome. We examined the intracellular localization of human Pellino-2 in THP1-derived macrophages during activation with LPS and ATP. We observed that Pellino-2 changed intracellular localization and colocalized with the inflammasome proteins NLRP3 and ASC late in the assembly of the inflammasome. Colocalization with NLRP3 and ASC was also seen in cells maintained in potassium-free medium. The colocalization and inflammasome activation were abrogated by several potassium channel inhibitors, supporting a role for potassium efflux in modulating intracellular localization of Pellino-2. The data suggest that Pellino-2 is essential for mediating the effect of potassium efflux on inflammasome activation.publishedVersio
IC3D Classification of Corneal Dystrophies-Edition 3
PURPOSE: The International Committee for the Classification of Corneal Dystrophies (IC3D) was created in 2005 to develop a new classification system integrating current information on phenotype, histopathology, and genetic analysis. This update is the third edition of the IC3D nomenclature.
METHODS: Peer-reviewed publications from 2014 to 2023 were evaluated. The new information was used to update the anatomic classification and each of the 22 standardized templates including the level of evidence for being a corneal dystrophy [from category 1 (most evidence) to category 4 (least evidence)].
RESULTS: Epithelial recurrent erosion dystrophies now include epithelial recurrent erosion dystrophy, category 1 ( COL17A1 mutations, chromosome 10). Signs and symptoms are similar to Franceschetti corneal dystrophy, dystrophia Smolandiensis, and dystrophia Helsinglandica, category 4. Lisch epithelial corneal dystrophy, previously reported as X-linked, has been discovered to be autosomal dominant ( MCOLN1 mutations, chromosome 19). Classic lattice corneal dystrophy (LCD) results from TGFBI R124C mutation. The LCD variant group has over 80 dystrophies with non-R124C TGFBI mutations, amyloid deposition, and often similar phenotypes to classic LCD. We propose a new nomenclature for specific LCD pathogenic variants by appending the mutation using 1-letter amino acid abbreviations to LCD. Pre-Descemet corneal dystrophies include category 1, autosomal dominant, punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) ( PRDX3 mutations, chromosome 10). Typically asymptomatic, it can be distinguished phenotypically from pre-Descemet corneal dystrophy, category 4. We include a corneal dystrophy management table.
CONCLUSIONS: The IC3D third edition provides a current summary of corneal dystrophy information. The article is available online at https://corneasociety.org/publications/ic3d
Elevated cholesterol in ATAD3 mutants is a compensatory mechanism that leads to membrane cholesterol aggregation
Aberrant cholesterol metabolism causes neurological disease and neurodegeneration, and mitochondria have been linked to perturbed cholesterol homeostasis via the study of pathological mutations in the ATAD3 gene cluster. However, whether the cholesterol changes were compensatory or contributory to the disorder was unclear, and the effects on cell membranes and the wider cell were also unknown.
Using patient-derived cells, we show that cholesterol perturbation is a conserved feature of pathological ATAD3 variants that is accompanied by an expanded lysosome population containing membrane whorls characteristic of lysosomal storage diseases. Lysosomes are also more numerous in Drosophila neural progenitor cells expressing mutant Atad3, which exhibit abundant membrane-bound cholesterol aggregates, many of which co-localize with lysosomes. By subjecting the Drosophila Atad3 mutant to nutrient restriction and cholesterol supplementation, we show that the mutant displays heightened cholesterol dependence.
Collectively, these findings suggest that elevated cholesterol enhances tolerance to pathological ATAD3 variants; however, this comes at the cost of inducing cholesterol aggregation in membranes, which lysosomal clearance only partly mitigates
Diagnosis and management in Rubinstein-Taybi syndrome:first international consensus statement
Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.</p
Diagnosis and management in Rubinstein-Taybi syndrome:first international consensus statement
Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.</p
Elevated cholesterol in ATAD3 mutants is a compensatory mechanism that leads to membrane cholesterol aggregation
Aberrant cholesterol metabolism causes neurological disease and neurodegeneration, and mitochondria have been linked to perturbed cholesterol homeostasis via the study of pathological mutations in the ATAD3 gene cluster. However, whether the cholesterol changes were compensatory or contributory to the disorder was unclear, and the effects on cell membranes and the wider cell were also unknown. Using patient-derived cells, we show that cholesterol perturbation is a conserved feature of pathological ATAD3 variants that is accompanied by an expanded lysosome population containing membrane whorls characteristic of lysosomal storage diseases. Lysosomes are also more numerous in Drosophila neural progenitor cells expressing mutant Atad3, which exhibit abundant membrane-bound cholesterol aggregates, many of which co-localize with lysosomes. By subjecting the Drosophila Atad3 mutant to nutrient restriction and cholesterol supplementation, we show that the mutant displays heightened cholesterol dependence. Collectively, these findings suggest that elevated cholesterol enhances tolerance to pathological ATAD3 variants; however, this comes at the cost of inducing cholesterol aggregation in membranes, which lysosomal clearance only partly mitigates.M.M.O. was supported by a predoctoral fellowship from the University of the Basque Country (PIF18/317) and later partially supported by the Ikerbasque, Basque Foundation for Science IKUR strategy Neurodegenprot project. A.L. and U.F.P. were recipients of pre-doctoral fellowships from the Basque Government (PRE_2019_1_0184 and PRE_2018_1_0253). The study was supported by funding to I.J.H. from the Instituto de Salud Carlos III (PI17-00380; PI20/00096) and the Basque Government Department of Health (Osasun Saila, Eusko Jaurlaritzako) (grants 2021111070; 2022333050; 2018111043; 2018222031). A.Sp. receives support from Miriam Marks Senior Fellowship, Brain Research UK (202021-26), the Research Councils UK (MR/X002365/1) and the Lily Foundation. W.H.Y. is supported by the National Institute of Neurological Disorders and Stroke (5R01 NS121298-03) of the National Institutes of Health, Oklahoma Center for Adult Stem Cell Research (OCASCR) (221009 and 241006) and Presbyterian Health Foundation (4411-09-10-0).Peer reviewe
Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement
Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care
Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement
Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care
Pellino-2 in nonimmune cells: novel interaction partners and intracellular localization
Pellino-2 is an E3 ubiquitin ligase that mediates intracellular signaling in innate immune pathways. Most studies of endogenous Pellino-2 have been performed in macrophages, but none in nonimmune cells. Using yeast two-hybrid screening and co-immunoprecipitation, we identified six novel interaction partners of Pellino-2, with various localizations: insulin receptor substrate 1, NIMA-related kinase 9, tumor necrosis factor receptor-associated factor 7, cyclin-F, roundabout homolog 1, and disheveled homolog 2. Pellino-2 showed cytoplasmic localization in a wide range of nonimmune cells under physiological potassium concentrations. Treatment with the potassium ionophore nigericin resulted in nuclear localization of Pellino-2, which was reversed by the potassium channel blocker tetraethylammonium. Live-cell imaging revealed intracellular migration of GFP-tagged Pellino-2. In summary, Pellino-2 interacts with proteins at different cellular locations, taking part in dynamic processes that change its intracellular localization influenced by potassium efflux
Functional characterization of all‐trans retinoic acid‐induced differentiation factor (ATRAID)
All‐trans retinoic acid‐induced differentiation (ATRAID) factor was first identified in HL60 cells. Several mRNA isoforms exist, but the respective proteins have not been fully characterized. In transfected cells expressing Myc‐Flag‐tagged ATRAID Isoform (Iso) A, B, and C, Iso C was found to be expressed at high levels, Iso A was found to be expressed at low levels due to rapid degradation, and the predicted protein expressed from Iso B was not detected. Iso C was present mainly in an N‐glycosylated form. In subcellular fractionation experiments, Iso C localized to the membranous and nuclear fractions, while immunofluorescence analysis revealed that Iso C is located close to the plasma membrane, mainly in cytoplasmic vesicles and in the Golgi area. We confirm that Iso C colocalizes to some extent with endosomal/lysosomal markers LAMP1 and LAMP2. Furthermore, we show that ATRAID co‐localizes with RAB11, a GTPase associated with recycling endosomes and implicated in regulating vesicular trafficking