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1.
Int J Mol Sci ; 21(17)2020 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-32824881

RESUMEN

ß-dystroglycan (ß-DG) assembles with lamins A/C and B1 and emerin at the nuclear envelope (NE) to maintain proper nuclear architecture and function. To provide insight into the nuclear function of ß-DG, we characterized the interaction between ß-DG and emerin at the molecular level. Emerin is a major NE protein that regulates multiple nuclear processes and whose deficiency results in Emery-Dreifuss muscular dystrophy (EDMD). Using truncated variants of ß-DG and emerin, via a series of in vitro and in vivo binding experiments and a tailored computational analysis, we determined that the ß-DG-emerin interaction is mediated at least in part by their respective transmembrane domains (TM). Using surface plasmon resonance assays we showed that emerin binds to ß-DG with high affinity (KD in the nanomolar range). Remarkably, the analysis of cells in which DG was knocked out demonstrated that loss of ß-DG resulted in a decreased emerin stability and impairment of emerin-mediated processes. ß-DG and emerin are reciprocally required for their optimal targeting within the NE, as shown by immunofluorescence, western blotting and immunoprecipitation assays using emerin variants with mutations in the TM domain and B-lymphocytes of a patient with EDMD. In summary, we demonstrated that ß-DG plays a role as an emerin interacting partner modulating its stability and function.


Asunto(s)
Distroglicanos/metabolismo , Proteínas de la Membrana/metabolismo , Distrofia Muscular de Emery-Dreifuss/metabolismo , Proteínas Nucleares/metabolismo , Transporte Activo de Núcleo Celular , Animales , Linfocitos B/metabolismo , Sitios de Unión , Línea Celular , Células Cultivadas , Distroglicanos/química , Distroglicanos/genética , Células HeLa , Humanos , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Ratones , Distrofia Muscular de Emery-Dreifuss/genética , Mutación , Membrana Nuclear/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/genética , Unión Proteica
2.
Aging Cell ; 18(5): e13002, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31305018

RESUMEN

The study of Hutchinson-Gilford progeria syndrome (HGPS) has provided important clues to decipher mechanisms underlying aging. Progerin, a mutant lamin A, disrupts nuclear envelope structure/function, with further impairment of multiple processes that culminate in senescence. Here, we demonstrate that the nuclear protein export pathway is exacerbated in HGPS, due to progerin-driven overexpression of CRM1, thereby disturbing nucleocytoplasmic partitioning of CRM1-target proteins. Enhanced nuclear export is central in HGPS, since pharmacological inhibition of CRM1 alleviates all aging hallmarks analyzed, including senescent cellular morphology, lamin B1 downregulation, loss of heterochromatin, nuclear morphology defects, and expanded nucleoli. Exogenous overexpression of CRM1 on the other hand recapitulates the HGPS cellular phenotype in normal fibroblasts. CRM1 levels/activity increases with age in fibroblasts from healthy donors, indicating that altered nuclear export is a common hallmark of pathological and physiological aging. Collectively, our findings provide novel insights into HGPS pathophysiology, identifying CRM1 as potential therapeutic target in HGPS.


Asunto(s)
Envejecimiento Prematuro/metabolismo , Núcleo Celular/metabolismo , Senescencia Celular , Carioferinas/metabolismo , Proteínas Nucleares/metabolismo , Progeria/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Transporte Activo de Núcleo Celular , Envejecimiento Prematuro/patología , Células Cultivadas , Humanos , Fenotipo , Progeria/patología , Proteína Exportina 1
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