Aging is characterized by a progressive decline in proteostasis, leading to protein misfolding and aggregation. Another emerging aspect of the age-related collapse of the proteostasis network is the loss of subcellular spatial distribution and dynamic transport of proteins across the nuclear pore. With the help of Ran GTPase, karyopherins (importins, exportins and biportins) mediate the transport of large proteins across the nuclear pore by recognizing localization motifs. During aging, changes in karyopherin levels and activity modify nuclear pore function and changes subcellular protein distribution, which in turn alters phase condensation and aggregation dynamics. Genetic and pharmacological modulations of key karyopherins, such as the exportin XPO,1 impacts proteostasis by not only re-distributing a subset of proteins, but also via transcriptional activation of the autophagy-lysosomal pathway by enriching the autophagy transcription factor HLH-30/TFEB in the nucleus. In addition, subcellular protein redistribution from XPO1 inhibition leads to major changes in nucleolar size dynamics, which consequently alters ribosomal biogenesis and translational efficiencies resulting in longer lifespan in C. elegans. Work in human cancer cells mirrors changes observed in C. elegans on TFEB and nucleolar modulation, and XPO1 inhibition in a model of Alzheimer's disease in mice improves spatial cognition. Altogether, karyopherin modulation is emerging as a novel point of entry to modulate proteostasis and autophagy against the progressive proteostatic decline in aging.

 

Invité par Audrey Esclatine (audrey.esclatine@i2bc.paris-saclay.fr)