2023
bioRxiv

Nuclear translocation of LINE-1 encoded ORF1p alters nuclear envelope integrity and disrupts nucleocytoplasmic transport in neurons

Authors:

Rania Znaidi, Olivia Massiani-Beaudoin, Philippe Mailly, Héloïse Monnet, Rajiv L. Joshi, Julia Fuchs

Keywords:

Retrotransposons, LINE-1, ORF1p, nuclear envelope, nuclear pore complex, nucleo-cytoplasmic transport, neurodegeneration

Abstract:

LINE-1 retrotransposons are emerging as possible culprits in neurodegenerative diseases. However, the molecular mechanisms underlying the pathogenic role of LINE-1 and their encoded proteins ORF1p and ORF2p are still not completely understood. While the endonuclease and reverse transcriptase activity of ORF2p has been associated with DNA damage and inflammation, no pathogenic role has yet been assigned to ORF1p. Using a neuronal model of oxidative stress displaying increased LINE-1 expression, we report here that ORF1p stress-dependently translocates into the nucleus, localizes to the nuclear envelope and directly binds to nuclear lamina (Lamin B1), nuclear pore complex (NUP153) components and nuclear import (KPNB1) proteins. Stress-dependent targeting of nuclear envelope components by ORF1p alters nuclear envelope integrity, disrupts nucleo-cytoplasmic transport and induces heterochromatin destructuration, which are key features associated with neurodegenerative diseases and aging. Interestingly, nuclear deformations and heterochromatin destructuration were restored by the small molecule Remodelin which also normalized nuclear ORF1p levels. This study thus reveals a retrotransposition-independent pathogenic action of ORF1p perturbing nuclear envelope barrier function.