The CPEB3 Protein Is a Functional Prion that Interacts with the Actin Cytoskeleton

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.

Prions, amyloids, and RNA: Pieces of a puzzle

“…169 Finally, three recent manuscripts analyzed aggregation and self-perpetuation of the mouse ortholog of ApCPEB, CPEB3. 59,162,163 Studies of an ectopically expressed purified protein confirmed the ability of CPEB3 to form typical amyloid fibers with a characteristic birefringence upon Congo Red staining. Studies in yeast established that CPEB3 can act as a bona fide prion, i.e.…”

“…58 Notably, analysis of amyloidogenic proteins reveals that some of them carry both types of CBRs / LCRs. 59 Computational prediction of amyloid properties is efficient for short peptides. The false positive rate for full-length proteins is much higher, 60 although some recently developed algorithms provide up to 70% of true positive predictions for full-length proteins.…”

“…63 Analogously, the prion domain of the CPEB3 protein carries two aggregation domains with non-identical roles in amyloid formation, which are separated by a module regulating aggregation by affecting CPEB3 interaction with the actin cytoskeleton. 59 One intriguing feature of the amyloid-forming proteins identified to date is a significant overrepresentation of mRNA-processing proteins. This peculiarity was first noted for Q/Nrich proteins of the yeast Saccharomyces cerevisiae, 53 and was later upheld for confirmed prions.…”

“…Remarkable examples of the translation-coupled functional amyloids in multicellular organisms are neuron-specific forms of the cytoplasmic polyadenylation element binding protein (CPEB), ApCPEB, Orb2, and CPEB3 in the mollusk Aplysia californica, 24,159,160 fruit fly Drosophila melanogaster, 161 and mouse, 59,162,163 correspondingly. CPEB represents a family of RNA-binding proteins that bind U-rich sequences called CPE elements, which are located in the 3 0 untranslated regions of a number of cellular mRNAs.…”

“…Noteworthy, in agreement with the hypothesis that the CPEB3 prion acts as a synaptic tag in the maintenance of long-term memory persistence, CPEB3 aggregation not only self-perpetuates, but also supports the translation of proteins essential for the functioning of the synapse, such as GluR receptors, as well as proteins essential for CPEB3 regulation, such as actin and SUMO. 59,162,163 Overall, CPEB proteins form functional amyloids with prion-like properties that control long-term memory and possess a complex regulatory network consisting of chemical and protein regulators.…”