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Phosphorylation-Mediated Clearance of Amyloid-like Assemblies in Meiosis
Kayla Carpenter1, Rachel Brietta Bell1, Julius Yunus1
1Department of Genetics and Development, Columbia University Medical Center, 701 W. 168th Street, Hammer Health Sciences Building, Room 1520, New York, NY 10032, USA.
Abstract:
Amyloids are fibrous protein assemblies that are often described as irreversible and intrinsically pathogenic. However, yeast cells employ amyloid-like assemblies of the RNA-binding protein Rim4 to control translation during meiosis. Here, we show that multi-site phosphorylation of Rim4 is critical for its regulated disassembly and degradation and that failure to clear Rim4 assemblies interferes with meiotic progression. Furthermore, we identify the protein kinase Ime2 to bring about Rim4 clearance via phosphorylation of Rim4's intrinsically disordered region. Rim4 phosphorylation leads to reversal of its amyloid-like properties and degradation by the proteasome. Our data support a model in which a threshold amount of phosphorylation, rather than modification of critical residues, is required for Rim4 clearance. Our results further demonstrate that at least some amyloid-like assemblies are not as irreversible as previously thought. We propose that the natural pathways by which cells process these structures could be deployed to act on disease-related amyloids.
Insights
Yeast cells can reversibly break down amyloid-like protein structures called Rim4 assemblies. This regulated process, controlled by phosphorylation, is crucial for successful cell division and offers insights into managing disease-related amyloids.
Area of Science:
- Cell Biology
- Molecular Biology
- Protein Biochemistry
Background:
- Amyloids are typically considered irreversible and pathogenic protein aggregates.
- Yeast utilize amyloid-like assemblies of the RNA-binding protein Rim4 for translational control during meiosis.
Purpose of the Study:
- To investigate the regulation of Rim4 amyloid-like assembly disassembly and degradation.
- To identify the molecular mechanisms governing Rim4 clearance during meiosis.
- To explore the implications of reversible amyloid-like structures for disease-related amyloids.
Main Methods:
- Investigated the role of multi-site phosphorylation in Rim4 assembly dynamics.
- Identified the protein kinase Ime2 as a key regulator of Rim4 clearance.
- Analyzed the impact of Rim4 clearance failure on meiotic progression using yeast models.
Main Results:
- Multi-site phosphorylation of Rim4 is essential for its regulated disassembly and proteasomal degradation.
- The protein kinase Ime2 mediates Rim4 clearance through phosphorylation of its intrinsically disordered region.
- Failure to degrade Rim4 assemblies impedes meiotic progression, indicating the necessity of clearance.
Conclusions:
- A threshold level of Rim4 phosphorylation, not specific residue modification, drives assembly clearance.
- Amyloid-like assemblies can be dynamically regulated and disassembled, challenging previous assumptions of irreversibility.
- Natural cellular pathways for amyloid-like structure processing may offer therapeutic strategies for amyloid diseases.
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