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

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.

Loss of Dystroglycan Drives Cellular Senescence via Defective Mitosis-Mediated Genomic Instability

“…Then, nuclear area and circularity parameters were calculated, as described previously [ 58 ]. The nucleolar area (μm 2 ) was calculated on maxima projection images, using a 3D objects counter, as described previously [ 59 ]. To quantify the fluorescence intensity of γ-H2AX (DNA-damage marker and H3K9me3 (heterochromatin marker) foci, the Find Maxima function from ImageJ was used, as previously described [ 60 ].…”

Protein structural and mechanistic basis of progeroid laminopathies

“…The nuclear import pathway mediated by transportin-1 is impaired [54]. CRM1-driven nuclear protein export may be abnormally enhanced [55].…”

Pharmacotherapy to gene editing: potential therapeutic approaches for Hutchinson–Gilford progeria syndrome

“…The overexpression of a protein exportin-1 or chromosomal region maintenance 1 (CRM1) caused by progerin expression leads to a disbalance in nuclear protein export, which is one of the central regulatory features of progeric phenotype (García-Aguirre et al 2019). Pharmacological inhibition of CRM1 with leptomycin B (LMB) can alleviate almost all significant pathophysiological features of HGPS in the cell viz.…”

“…nuclear blebbing, reduced lamin B1 expression, cellular senescence, heterochromatin loss, expansion of nucleoli, etc. Since enhanced nuclear export due to enhanced CRM1 activity is now considered as key converging mechanism in pathological and normal aging, targeting this molecule can significantly attenuate the progression of the disorder (García-Aguirre et al 2019).…”

“…There are several other cellular and molecular consequences that result in the pathophysiology of this disease at the cellular and systemic levels. These changes include disruption of nucleocytoplasmic Ran gradient (Kelley et al 2011), disturbance in nuclear export (García-Aguirre et al 2019), alteration in microtubular network (Larrieu et al 2018), defective polarity (Chang et al 2019), reduction in autophagic proteolysis (Lu and Djabali 2018), mitochondrial dysfunction and oxidative stress (Kubben et al 2016;Rivera-Torres et al 2013;Sieprath et al 2015), lowered PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) expression level (Xiong et al 2016), stress in the endoplasmic reticulum (ER) and unfolded protein response (Hamczyk et al 2019), DNA damage (Gonzalo and Kreienkamp 2015;Liu et al 2005), shortening of telomeres (Gonzalez-Suarez et al 2009), defects in purine synthesis (Mateos et al 2018), loss of peripheral heterochromatin (Gesson et al 2016), impaired epigenetic regulation (Shumaker et al 2006), chromatin remodeling (Pegoraro et al 2009), alteration in cell signaling pathways (Aliper et al 2015), inhibition of cell cycle progression and increased apoptosis (Bridger and Kill 2004), leakage of DNA into cytoplasm (Kreienkamp et al 2018), upregulation of inflammatory pathways (Osorio et al 2012), depletion of stem cell reserves for tissue repairing (Rosengardten et al 2011), defects in self-renewal and differentiation capacity of stem cells, and disbalance in the synthesis of extracellular matrix (ECM) components and remodeling enzymes (Csoka et al 2004;Vidak et al 2015).…”