Amyloidogenic Oligomerization Transforms Drosophila Orb2 from a Translation Repressor to an Activator

Khan, Mohammed Repon; Li, Liying; Pérez-Sánchez, Consuelo; Saraf, Anita; Florens, Laurence; Slaughter, Brian D.; Unruh, Jay R.; Si, Kausik

doi:10.1016/j.cell.2015.11.020

Cited by 101 publications

(135 citation statements)

References 46 publications

Supporting

Mentioning

132

Contrasting

Order By: Relevance

“…S4). Also in support of these findings, a previously identified Orb2 target Tequila (26) has been recently reported to require a G-containing but not the A-containing CPE motif for binding to Orb2 (34). Our data supports a model in which CPEB paralogues display a preferential specificity for distinct CPE versions that must be confirmed by further biochemical studies.…”

Section: Discussionsupporting

confidence: 89%

“…S1 A and C), reminiscent of the endogenous Orb2 protein in Drosophila brain in vivo (20). CPEB aggregates are thought to be associated with their normal function, including LTM, and to be mediated by the poly-Q domain (20,(32)(33)(34). In comparison, Orb mRNA is not expressed in S2 cells (average RPKM = 0.1; n = 2), although the majority of its known interactors (88%) are present (RPKM >1) (35,36).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

RNA-binding profiles of Drosophila CPEB proteins Orb and Orb2

Stepien

Oppitz

Gerlach

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Localized protein translation is critical in many biological contexts, particularly in highly polarized cells, such as neurons, to regulate gene expression in a spatiotemporal manner. The cytoplasmic polyadenylation element-binding (CPEB) family of RNA-binding proteins has emerged as a key regulator of mRNA transport and local translation required for early embryonic development, synaptic plasticity, and long-term memory (LTM). Drosophila Orb and Orb2 are single members of the CPEB1 and CPEB2 subfamilies of the CPEB proteins, respectively. At present, the identity of the mRNA targets they regulate is not fully known, and the binding specificity of the CPEB2 subfamily is a matter of debate. Using transcriptome-wide UV cross-linking and immunoprecipitation, we define the mRNA-binding sites and targets of Drosophila CPEBs. Both Orb and Orb2 bind linear cytoplasmic polyadenylation element-like sequences in the 3′ UTRs of largely overlapping target mRNAs, with Orb2 potentially having a broader specificity. Both proteins use their RNA-recognition motifs but not the Zinc-finger region for RNA binding. A subset of Orb2 targets is translationally regulated in cultured S2 cells and fly head extracts. Moreover, pan-neuronal RNAi knockdown of these targets suggests that a number of these targets are involved in LTM. Our results provide a comprehensive list of mRNA targets of the two CPEB proteins in Drosophila, thus providing insights into local protein synthesis involved in various biological processes, including LTM.CPEB | CLIP | Orb2 | translation | long-term memory

show abstract

Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

RNA-binding profiles of Drosophila CPEB proteins Orb and Orb2

Stepien

Oppitz

Gerlach

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Deadenylation by the monomer is mediated by CG13928 and the translational activity of oligomeric Orb2 is mediated by CG4612, which is also required for LTM formation. 151 These observations suggest that in the basal state Orb2 binds mRNA and keeps them in a repressed state with the help of the deadenylation complex, and upon activation oligomerization initiates translation of mRNAs that were previously sequestered in repressed state.…”

Section: Cpeb1 In Drosophila -Orb2mentioning

confidence: 96%

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

Sudhakaran

Ramaswami

2016

RNA Biology

View full text Add to dashboard Cite

Long-term and short-term memories differ primarily in the duration of their retention. At a molecular level, long-term memory (LTM) is distinguished from short-term memory (STM) by its requirement for new gene expression. In addition to transcription (nuclear gene expression) the translation of stored mRNAs is necessary for LTM formation. The mechanisms and functions for temporal and spatial regulation of mRNAs required for LTM is a major contemporary problem, of interest from molecular, cell biological, neurobiological and clinical perspectives. This review discusses primary evidence in support for translational regulatory events involved in LTM and a model in which different phases of translation underlie distinct phases of consolidation of memories. However, it focuses largely on mechanisms of memory persistence and the role of prion-like domains in this defining aspect of long-term memory. We consider primary evidence for the concept that Cytoplasmic Polyadenylation Element Binding (CPEB) protein enables the persistence of formed memories by transforming in prion-like manner from a soluble monomeric state to a self-perpetuating and persistent polymeric translationally active state required for maintaining persistent synaptic plasticity. We further discuss prion-like domains prevalent on several other RNA-binding proteins involved in neuronal translational control underlying LTM. Growing evidence indicates that such RNA regulatory proteins are components of mRNP (RiboNucleoProtein) granules. In these proteins, prion-like domains, being intrinsically disordered, could mediate weak transient interactions that allow the assembly of RNP granules, a source of silenced mRNAs whose translation is necessary for LTM. We consider the structural bases for RNA granules formation as well as functions of disordered domains and discuss how these complicate the interpretation of existing experimental data relevant to general mechanisms by which prion-domain containing RBPs function in synapse specific plasticity underlying LTM.

show abstract

“…However, the evolutionary breadth of this mechanism is unknown and its biological significance is highly controversial (McGlinchey et al, 2011; Nakayashiki et al, 2005). Although some prions have been proposed to have adaptive value (Jarosz et al, 2014a; Khan et al, 2015; Suzuki et al, 2012; True and Lindquist, 2000), this paradigm-shifting mechanism of inheritance was discovered as a mechanism for the transmission of a devastating spongiform encephalopathy (Prusiner, 1982). …”

Section: Introductionmentioning

confidence: 99%

Intrinsically Disordered Proteins Drive Emergence and Inheritance of Biological Traits

Chakrabortee

Byers

Jones

et al. 2016

Cell

174

232

View full text Add to dashboard Cite

Summary Prions are a paradigm-shifting mechanism of inheritance in which phenotypes are encoded by self-templating protein conformations rather than nucleic acids. Here we examine the breadth of protein-based inheritance across the yeast proteome by assessing the ability of nearly every open reading frame (∼5,300 ORFs) to induce heritable traits. Transient overexpression of nearly 50 proteins created traits that remained heritable long after their expression returned to normal. These traits were beneficial, had prion-like patterns of inheritance, were common in wild yeasts, and could be transmitted to naïve cells with protein alone. Most inducing proteins were not known prions and did not form amyloid. Instead, they are highly enriched in nucleic acid binding proteins with large intrinsically disordered domains that have been widely conserved across evolution. Our data thus establish a common type of protein-based inheritance through which intrinsically disordered proteins can drive the emergence of new traits and adaptive opportunities.

show abstract

Amyloidogenic Oligomerization Transforms Drosophila Orb2 from a Translation Repressor to an Activator

Cited by 101 publications

References 46 publications

RNA-binding profiles of Drosophila CPEB proteins Orb and Orb2

RNA-binding profiles of Drosophila CPEB proteins Orb and Orb2

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

Intrinsically Disordered Proteins Drive Emergence and Inheritance of Biological Traits

Contact Info

Product

Resources

About