PQBP3 prevents senescence by suppressing PSME3-mediated proteasomal Lamin B1 degradation.

Senescence of nondividing neurons remains an immature concept, with especially the regulatory molecular mechanisms of senescence-like phenotypes and the role of proteins associated with neurodegenerative diseases in triggering neuronal senescence remaining poorly explored. In this study, we reveal that the nucleolar polyglutamine binding protein 3 (PQBP3; also termed NOL7), which has been linked to polyQ neurodegenerative diseases, regulates senescence as a gatekeeper of cytoplasmic DNA leakage. PQBP3 directly binds PSME3 (proteasome activator complex subunit 3), a subunit of the 11S proteasome regulator complex, decreasing PSME3 interaction with Lamin B1 and thereby preventing Lamin B1 degradation and senescence. Depletion of endogenous PQBP3 causes nuclear membrane instability and release of genomic DNA from the nucleus to the cytosol. Among multiple tested polyQ proteins, ataxin-1 (ATXN1) partially sequesters PQBP3 to inclusion bodies, reducing nucleolar PQBP3 levels. Consistently, knock-in mice expressing mutant Atxn1 exhibit decreased nuclear PQBP3 and a senescence phenotype in Purkinje cells of the cerebellum. Collectively, these results suggest homologous roles of the nucleolar protein PQBP3 in cellular senescence and neurodegeneration. Synopsis: Senescence of nondividing cells such as neurons is thought to promote neurodegenerative diseases, however, its molecular control remains unclear. Here, the nucleolar protein PQBP3 (also termed NOL7), associated with polyQ diseases, is shown to prevent cellular senescence by antagonising genomic DNA leakage to the cytosol. PQBP3 is an intrinsically disordered protein localized primarily at the periphery of the nucleolus. PQBP3 depletion increases nuclear membrane instability and cytoplasmic DNA leakage in human cells, inducing senescence. PQBP3 interacts with the proteasome activator subunit PSME3, stabilizing Lamin B1 and the nuclear membrane. Decreased nuclear PQBP3, the polyQ protein ATXN1, and cellular senescence are associated with polyQ disease pathology in cerebellar Purkinje cells in mice. The nucleolar polyQ-binding protein PQBP3/NOL7 protects neurons from cellular senescence by stabilizing the nuclear membrane and preventing genomic DNA leakage. [ABSTRACT FROM AUTHOR]