Faculty, Staff and Student Publications
Publication Date
7-8-2022
Journal
Nucleic Acids Research
Abstract
The nucleolus is a subnuclear membraneless compartment intimately involved in ribosomal RNA synthesis, ribosome biogenesis and stress response. Multiple optogenetic devices have been developed to manipulate nuclear protein import and export, but molecular tools tailored for remote control over selective targeting or partitioning of cargo proteins into subnuclear compartments capable of phase separation are still limited. Here, we report a set of single-component photoinducible nucleolus-targeting tools, designated pNUTs, to enable rapid and reversible nucleoplasm-to-nucleolus shuttling, with the half-lives ranging from milliseconds to minutes. pNUTs allow both global protein infiltration into nucleoli and local delivery of cargoes into the outermost layer of the nucleolus, the granular component. When coupled with the amyotrophic lateral sclerosis (ALS)-associated C9ORF72 proline/arginine-rich dipeptide repeats, pNUTs allow us to photomanipulate poly-proline-arginine nucleolar localization, perturb nucleolar protein nucleophosmin 1 and suppress nascent protein synthesis. pNUTs thus expand the optogenetic toolbox by permitting light-controllable interrogation of nucleolar functions and precise induction of ALS-associated toxicity in cellular models.
Keywords
Amyotrophic Lateral Sclerosis, C9orf72 Protein, Cell Nucleolus, Drug Delivery Systems, Humans, Nuclear Proteins, Optogenetics, Protein Synthesis Inhibitors
DOI
10.1093/nar/gkac191
PMID
35325178
PMCID
PMC9262612
PubMedCentral® Posted Date
3-23-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes