Functional organization of promyelocytic leukemia bodies during proteotoxic stress


Promyelocytic leukemia (PML) nuclear bodies act as quality control centers in the nucleus, participating in a plethora of nuclear functions. As such, PML bodies are a signature model for functional nuclear organization. PML bodies have a dynamic protein composition that responds to changing conditions of the cell. Many of the protein binding-partners of PML have been functionally characterized into a SUMO-depended post-translational modification pathway for proteins. However, others such as nascent mRNA and translation machinery, suggest an additional uncharacterized function of PML-localized translation. Growing evidence supports the presence of translation in the eukaryotic nucleus, yet a clear demonstration of its functional relevance remains to be established. Here we demonstrate that nuclear polypeptides synthesized localizes to PML bodies during cell stress. Analysis of proteotoxic stress associated with the expression of mutant Ataxin-1 (ATXN1), a gene that causes the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1), reveals that PML bodies couple polypeptide synthesis with mRNA surveillance and protein quality control. Specifically, we find repeat-expanded ATXN1 mRNA foci and protein aggregates localized at PML bodies where they are subject to regulation by the no-go decay (NGD) pathway and protein degradation. To expand upon our mechanistic study, we identify protein binding-partners of PML during different cell stressors using an unbiased proteomics approach. Our study suggests a novel PML-localized regulatory system underlying nuclear translation that plays a critical role in the cell stress response.

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