Subcellular localization and RNAs determine FUS architecture in different cellular compartments

Liuqing Yang, Jiayu Zhang, Marisa Kamelgarn, Chunyan Niu, Jozsef Gal, Weimin Gong, Haining Zhu

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Mutations in Fused in sarcoma (FUS) gene cause a subset of familial amyotrophic lateral sclerosis (ALS), a fatal motor neuron degenerative disease. Wild-type FUS is largely localized in the nucleus, but mutant FUS accumulates in the cytoplasm and forms inclusions. It is unclear whether FUS depletion from the nucleus or FUS inclusions in the cytoplasm triggers motor neuron degeneration. In this study, we revealed that the nuclear and cytoplasmic FUS proteins form distinct local distribution patterns. The nuclear FUS forms oligomers and appears granular under confocal microscope. In contrast, the cytoplasmic FUS forms inclusions with no oligomers detected. These patterns are determined by the subcellular localization of FUS, regardless of wild-type or mutant protein. Moreover, mutant FUS remained or re-directed in the nucleus can oligomerize and behave similarly to the wild-type FUS protein. We further found that nuclear RNAs are critical to its oligomerization. Interestingly, the formation of cytoplasmic FUS inclusions is also dependent on RNA binding. Since the ALS mutations disrupt the nuclear localization sequence, mutant FUS is likely retained in the cytoplasm after translation and interacts with cytoplasmic RNAs. We therefore propose that local RNA molecules interacting with the FUS protein in different subcellular compartments play a fundamental role in determining FUS protein architecture and function.

Original languageEnglish (US)
Pages (from-to)5174-5183
Number of pages10
JournalHuman molecular genetics
Volume24
Issue number18
DOIs
StatePublished - Apr 9 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint

Dive into the research topics of 'Subcellular localization and RNAs determine FUS architecture in different cellular compartments'. Together they form a unique fingerprint.

Cite this