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

Author:

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 [ORCID]
Author Address

Department of Genetics and Molecular Biology, Center of Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico., Laboratory of Protein Dynamics and Signaling, Center for Cancer Research-Frederick, National Cancer Institute, National Institutes of Health, Frederick, MD, USA., Department of Biomedical Science, University of Sheffield, Sheffield, UK., Department of Cognitive Neuroscience, Institute of Cellular Physiology, National Autonomous University of Mexico (UNAM), Mexico City, Mexico., Department of Toxicology, Center of Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico., Laboratory of Genomic Medicine, Department of Genetics, National Rehabilitation Institute, "Luis Guillermo Ibarra Ibarra", Mexico City, Mexico.,

Abstract:

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. © 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

See More

Author Address