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The CPEB3 Protein Is a Functional Prion that Interacts with the Actin Cytoskeleton
Joseph S Stephan1, Luana Fioriti2, Nayan Lamba2
1Department of Neuroscience, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA; Howard Hughes Medical Institute, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA.
Abstract:
The mouse cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is a translational regulator implicated in long-term memory maintenance. Invertebrate orthologs of CPEB3 in Aplysia and Drosophila are functional prions that are physiologically active in the aggregated state. To determine if this principle applies to the mammalian CPEB3, we expressed it in yeast and found that it forms heritable aggregates that are the hallmark of known prions. In addition, we confirm in the mouse the importance of CPEB3's prion formation for CPEB3 function. Interestingly, deletion analysis of the CPEB3 prion domain uncovered a tripartite organization: two aggregation-promoting domains surround a regulatory module that affects interaction with the actin cytoskeleton. In all, our data provide direct evidence that CPEB3 is a functional prion in the mammalian brain and underline the potential importance of an actin/CPEB3 feedback loop for the synaptic plasticity underlying the persistence of long-term memory.
Insights
Mouse cytoplasmic polyadenylation element-binding protein 3 (CPEB3) functions as a prion in the brain, forming aggregates crucial for long-term memory. This prion activity involves actin interactions, potentially driving synaptic plasticity.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is a key translational regulator involved in maintaining long-term memory.
- Invertebrate CPEB3 proteins function as physiologically active prions in their aggregated state.
Purpose of the Study:
- To investigate whether mammalian CPEB3 also functions as a prion.
- To determine the role of CPEB3 prion formation in its overall function within the mouse brain.
Main Methods:
- Expressed mouse CPEB3 in yeast to observe aggregate formation.
- Performed deletion analysis of the CPEB3 prion domain.
- Confirmed the importance of prion formation for CPEB3 function in mice.
Main Results:
- Mouse CPEB3 forms heritable aggregates in yeast, characteristic of prions.
- CPEB3 prion formation is essential for its function in mice.
- The CPEB3 prion domain has a tripartite structure with aggregation-promoting regions and a regulatory module interacting with the actin cytoskeleton.
Conclusions:
- Mouse CPEB3 is a functional prion in the mammalian brain.
- A feedback loop between actin and CPEB3 may be vital for synaptic plasticity and long-term memory persistence.
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