Enhanced nuclear protein export in premature aging and rescue of the progeria phenotype by modulation of CRM1 activity

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 th...

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Bibliographic Details
Published in:Aging cell 2019-10, Vol.18 (5), p.e13002-n/a
Main Authors: García‐Aguirre, Ian, Alamillo‐Iniesta, Alma, Rodríguez‐Pérez, Ruth, Vélez‐Aguilera, Griselda, Amaro‐Encarnación, Elianeth, Jiménez‐Gutiérrez, Elizabeth, Vásquez‐Limeta, Alejandra, Samuel Laredo‐Cisneros, Marco, Morales‐Lázaro, Sara L., Tiburcio‐Félix, Reynaldo, Ortega, Arturo, Magaña, Jonathan J, Winder, Steve J., Cisneros, Bulmaro
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus
Aging
Aging, Premature - metabolism
Aging, Premature - pathology
Analysis
Cell Nucleus - metabolism
Cells, Cultured
Cellular Senescence
Exportin 1 Protein
exportin CRM1
Exports
Fibroblasts
Genetic aspects
Heterochromatin
Humans
Hutchinson‐Gilford progeria syndrome
Karyopherins - metabolism
lamin B1
Morphology
Nuclear Proteins - metabolism
Nuclear transport
Nucleoli
Original
Phenotype
Phenotypes
Physiological aspects
Progeria
Progeria - metabolism
Progeria - pathology
progerin
Protein transport
Proteins
Receptors, Cytoplasmic and Nuclear - metabolism
Senescence
Structure-function relationships
Therapeutic applications
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Summary: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. HGPS cells show enhanced nuclear protein export activity due to CRM1 overexpression. Ectopic overexpression of CRM1 recreates HGPS‐associated aging features in normal cells. Pharmacological modulation of CRM1 activity alleviates the HGPS phenotype.
ISSN:1474-9718
1474-9726
DOI:10.1111/acel.13002