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RNA-Binding Protein TAF15 Suppresses Toxicity in a Yeast Model of FUS Proteinopathy
Elliott Hayden1, Aicha Kebe1, Shuzhen Chen1
1Department of Biological Sciences, Wright State University, Dayton, OH 45435, USA.
Abstract:
Mutations in an RNA-binding protein FUS are known to cause familial amyotrophic lateral sclerosis (ALS). Since this discovery, mutations in several other RNA-binding proteins (RBPs) have also been linked to ALS. Some of these ALS-associated RBPs have been shown to colocalize with ribonucleoprotein (RNP) granules such as stress granules and processing bodies (p-bodies). Increasing evidence has emerged supporting a hypothesis that the impaired clearance, inappropriate assembly, and dysregulation of RNP granules play a role in ALS. Through the genome-scale overexpression screening of a yeast model of FUS toxicity, we found that TAF15, a human RBP with a similar protein domain structure and belonging to the same FET protein family as FUS, suppresses FUS toxicity in yeast. The suppression by TAF15 is specific to FUS and not found in other yeast models of neurodegenerative disease-associated proteins. We showed that the RNA recognition motif (RRM) of TAF15 is required for its suppression of FUS toxicity. Furthermore, FUS and TAF15 physically interact, and the C-terminus of TAF15 is required for both the physical protein-protein interaction and its protection against FUS toxicity. Finally, while FUS induces and colocalizes with both stress granules and p-bodies, TAF15 only induces and colocalizes with p-bodies. Importantly, the co-expression of FUS and TAF15 induces more p-bodies than individually expressing each gene alone, and FUS toxicity is exacerbated in yeast that is deficient in p-body formation. Overall, our findings suggest a role of increased p-body formation in the suppression of FUS toxicity by TAF15.
Insights
TAF15, an RNA-binding protein, suppresses FUS toxicity in yeast models of amyotrophic lateral sclerosis (ALS). This protective effect involves increased processing body (p-body) formation, highlighting a potential therapeutic strategy for ALS.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Mutations in RNA-binding proteins (RBPs), including FUS, are linked to familial amyotrophic lateral sclerosis (ALS).
- Dysregulation of ribonucleoprotein (RNP) granules, such as stress granules and processing bodies (p-bodies), is implicated in ALS pathogenesis.
- RBPs associated with ALS often colocalize with RNP granules.
Purpose of the Study:
- To investigate the role of TAF15, a FET family RBP, in suppressing FUS-induced toxicity in a yeast model.
- To elucidate the molecular mechanisms underlying TAF15's protective effect against FUS toxicity.
Main Methods:
- Genome-scale overexpression screening in a yeast model of FUS toxicity.
- Assessing the requirement of TAF15's RNA recognition motif (RRM) and C-terminus for suppression.
- Investigating the interaction between FUS and TAF15 and their colocalization with RNP granules.
- Analyzing the impact of TAF15 co-expression on FUS toxicity and p-body formation.
Main Results:
- TAF15 specifically suppresses FUS toxicity in yeast, unlike other neurodegenerative disease-associated proteins.
- The RRM and C-terminus of TAF15 are crucial for its protective function and physical interaction with FUS.
- FUS induces both stress granules and p-bodies, while TAF15 primarily induces and colocalizes with p-bodies.
- Co-expression of FUS and TAF15 enhances p-body formation, and p-body deficiency exacerbates FUS toxicity.
Conclusions:
- TAF15 suppresses FUS toxicity through mechanisms involving p-body formation.
- Increased p-body formation may serve as a protective response against FUS-mediated neurodegeneration.
- TAF15 represents a potential therapeutic target for ALS associated with FUS mutations.
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