2018 Dec 4;115(49):E11485-E11494.
doi: 10.1073/pnas.1811997115.
Epub 2018 Nov 15.
Ubiquilin 2 Modulates ALS/FTD-linked FUS-RNA Complex Dynamics and Stress Granule Formation
PMID:
30442662
PMCID: PMC6298105
DOI: 10.1073/pnas.1811997115
Free PMC article
Abstract
The ubiquitin-like protein ubiquilin 2 (UBQLN2) has been
genetically and pathologically linked to the neurodegenerative diseases
amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD),
but its normal cellular functions are not well understood. In a search
for UBQLN2-interacting proteins, we found an enrichment of stress
granule (SG) components, including ALS/FTD-linked heterogeneous
ribonucleoprotein fused in sarcoma (FUS) (FUS gene 16p11.2) . Through the use of an
optimized SG detection method, we observed UBQLN2 and its interactors at
SGs. A low complexity, Sti1-like repeat region in UBQLN2 was sufficient
for its localization to SGs. Functionally, UBQLN2 negatively regulated
SG formation. UBQLN2 increased the dynamics of FUS-RNA interaction and
promoted the fluidity of FUS-RNA complexes at a single-molecule level.
This solubilizing effect corresponded to a dispersal of FUS liquid
droplets in vitro and a suppression of FUS SG formation in cells.
ALS-linked mutations in UBQLN2 reduced its association with FUS and
impaired its function in regulating FUS-RNA complex dynamics and SG
formation. These results reveal a previously unrecognized role for
UBQLN2 in regulating the early stages of liquid-liquid phase separation
by directly modulating the fluidity of protein-RNA complexes and the
dynamics of SG formation.
Keywords:
ALS; FTD; FUS; stress granule; ubiquilin 2.
Conflict of interest statement
The authors declare no conflict of interest.
UBQLN2 geeni, NEDD4-sitova proteiini N4BP4 , ALS15
