Thursday, April 3, 2025
4/3/2025
Cathepsin-L mediated remodeling of the nuclear proteome - PROJECT SUMMARY: Gain- and loss-of function of architectural nuclear proteins lamin- A/C, -B1, -B2 are linked to both physiological aging and aging comorbidities such as cardiovascular disease, neurodegeneration, and cancer. Mutations in the LMNA gene cause devastating premature aging diseases: Hutchinson Gilford Progeria Syndrome (HGPS), Restrictive Dermopathy, and Atypical Werner Syndrome (AWS). Degradation of lamin B1 protein plays a major role in Alzheimer’s disease (AD). Accordingly, much emphasis is placed on identifying sorely needed therapeutic strategies to reduce the toxicity caused by lamins’ dysfunction. Here, pilot studies in HGPS patients-derived fibroblasts identified an unexpected mechanism to reduce the toxicity of progerin (lamin A mutant protein that causes HGPS): we found that treating these progerin-expressing cells with chloroquine robustly ameliorates aging hallmarks of progeria via upregulation and nuclear localization of the protease cathepsin L (CTSL). We provide evidence that CTSL modifies the C-terminal toxic tail of progerin, yet the mechanism remains to be elucidated. This discovery is highly significant because our studies in last decade have recurrently found a similar upregulation of nuclear CTSL under different contexts of nuclear damage and cellular stress, including lamin A/C loss, BRCA loss, oncogenic Ras expression, and starvation. In all those contexts, CTSL directly cleaves proteins that play key roles in DNA repair, cell cycle regulation, chromatin structure, and gene transcription. Altogether, these data suggest that activation of nuclear CTSL and CTSL-mediated remodeling of the nuclear proteome is a key event in the cellular response to stresses of different etiologies. In some contexts, nuclear CTSL may promote restoration of the damaged genome/lamina, reduction of nuclear defects, and improvement of cellular health; while in others, it may lead to elimination of the damaged cell by apoptosis or its growth arrest by senescence. Given the association of laminopathies with over twenty-five different degenerative disorders, cancer, and accelerated aging, understanding how nuclear CTSL modulates lamin/progerin processing (aim 1) and functional interactions (aim 2), and understanding nuclear CSTL substrate degradome under different stress conditions (aim 3) will have a profound and sustained impact across disciplines by advancing our understanding of cellular responses to nuclear damage.
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