Dataset Information

Exportin 1 modulates lifespan by regulating nucleolar dynamics via the autophagy protein LGG-1/GABARAP

ABSTRACT: Altered nucleolar and ribosomal dynamics are key hallmarks of aging, but their regulation remains unclear. Building on the knowledge that the conserved nuclear export receptor Exportin 1 (XPO-1/XPO1) modulates proteostasis and lifespan, we systematically analyzed the impact of nuclear export on protein metabolism. Using transcriptomic and subcellular proteomic analyses in nematodes, we demonstrate that XPO-1 modulates the nucleo-cytoplasmic distribution of key proteins involved in nucleolar dynamics and ribosome function, including fibrillarin (FIB-1/FBL) and RPL-11 (RPL11). Silencing XPO-1 led to marked reduction in global translation, which was accompanied by decreased nucleolar size and lower fibrillarin levels. A targeted screen of known proteostatic mediators revealed that the autophagy protein LGG-1/GABARAP modulates nucleolar size by regulating RPL-11 levels, linking specific protein degradation to ribosome metabolism. Altogether, our study reveals that nucleolar size, and consequently lifespan, are regulated by LGG-1/GABARAP via ribosome protein surveillance.

INSTRUMENT(S):

ORGANISM(S): Caenorhabditis Elegans

SUBMITTER: Taewook Kang

LAB HEAD: Louis R Lapierre

PROVIDER: PXD027230 | Pride | 2026-02-23

REPOSITORIES: Pride

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Exportin 1 modulates life span by regulating nucleolar dynamics via the autophagy protein LGG-1/GABARAP.

Kumar Anita V AV Kang Taewook T Thakurta Tara G TG Ng Celeste C Rogers Aric N AN Larsen Martin R MR Lapierre Louis R LR

Science advances 20220401 13

Altered nucleolar and ribosomal dynamics are key hallmarks of aging, but their regulation remains unclear. Building on the knowledge that the conserved nuclear export receptor Exportin 1 (XPO-1/XPO1) modulates proteostasis and life span, we systematically analyzed the impact of nuclear export on protein metabolism. Using transcriptomic and subcellular proteomic analyses in nematodes, we demonstrate that XPO-1 modulates the nucleocytoplasmic distribution of key proteins involved in nucleolar dyna ...[more]

PMID: 35363528

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Project description:The nucleolus is a dynamic structure where ribosome subunits are produced. Indeed, nucleoli respond to any change in cellular homeostasis by altering the rate of ribosome biogenesis, thus working as a stress sensor. Consequently, imbalances in ribosome biogenesis promotes changes in morphology and function and can evoke a nucleolar stress and DNA damage responses. These changes in nucleolar architecture and composition, culminating in impaired ribosome biogenesis, prompt the emergence of the nucleolar stress, which manifests as a contributing factor in aging and cancer. Here, we illuminate the pivotal role that the RNA binding protein Hnrnpk plays in orchestrating nucleolar dynamics and sustaining ribosome function. As a ribonucleoprotein, Hnrnpk governs the chaperoning of nascent transcripts to facilitate their processing and subsequent nuclear export for ribosomal integration. When overexpressed, Hnrnpk induces disruptive alterations in nucleolar structure, resulting in stress-like phenotypes; such as unbalances of molecular components, accumulation and delocalization of nucleolin, and decrease expression and occupation of fibrillarin. Consequentially, these aberrations in nucleolar equilibrium engenders a disruption in ribosome biogenesis and concomitantly halts the protein translation machinery. Nucleolin (Ncl) haploinsufficiency is correlated with enlarged nucleoli, increased ribosome components, heightened translational rates translation and a concomitant decrease in lifespan. Thus, an Hnrnpk overexpression-dependent surge of Ncl levels stemming may instigate a decline in nucleolar integrity and perturbations in ribosome biogenesis—an event intimately associated with ribosomopathies and the ensuing syndrome of bone marrow failure syndrome. Intersting, the aging process shares a number of common biological hallmarks with bone marrow failure. Again, alterations in Hnrnpk expression, specifically overexpression triggers nucleolar stress, driving cell cycle arrest and senescence of the cells. Our investigations demonstrate that p53, c-Myc and Ncl haploinsufficiency rescue these Hnrnpk-mediated phenotypes. Collectively, the data begin to decipher novel signaling pathway involved in nucleolar stress - ribosome stress – and p53 driven cell cycle arrest that governs this process. Together, these findings support the idea that nucleolar disturbances contribute to ribosome impairment, thus catalyzing the genesis of hematopoietic anomalies and aging process. Significantly, this study elucidates Hnrnpk as a previously unrecognized master regulator within these intricate ribosomal mechanisms; providing a novel window to view the orchestration of nucleolar integrity, ribosome function, and cellular senescence.

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