NMDAR signaling facilitates the IPO5-mediated nuclear import of CPEB3

Chao, Hsu; Lai, Yen-Ting; Lu, Yi-Ling; Lin, Chi Long; Mai, Weiyi; Huang, Yi

doi:10.1093/nar/gks598

Cited by 48 publications

(74 citation statements)

References 43 publications

(71 reference statements)

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“…Figure 3a shows the myc-tagged wt and RRM1-deleted mutant CPEB3 used as the positive and negative controls for RNA binding, respectively (48). The RNA binding and expression of the CPEB3 mutants were examined by UV-cross-linking RNA-binding assay and western blotting, respectively (Figure 3b).…”

Section: Resultsmentioning

confidence: 99%

Identifying RNA-binding residues based on evolutionary conserved structural and energetic features

Chen

Sargsyan

Wright

et al. 2013

Nucleic Acids Research

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Increasing numbers of protein structures are solved each year, but many of these structures belong to proteins whose sequences are homologous to sequences in the Protein Data Bank. Nevertheless, the structures of homologous proteins belonging to the same family contain useful information because functionally important residues are expected to preserve physico-chemical, structural and energetic features. This information forms the basis of our method, which detects RNA-binding residues of a given RNA-binding protein as those residues that preserve physico-chemical, structural and energetic features in its homologs. Tests on 81 RNA-bound and 35 RNA-free protein structures showed that our method yields a higher fraction of true RNA-binding residues (higher precision) than two structure-based and two sequence-based machine-learning methods. Because the method requires no training data set and has no parameters, its precision does not degrade when applied to ‘novel’ protein sequences unlike methods that are parameterized for a given training data set. It was used to predict the ‘unknown’ RNA-binding residues in the C-terminal RNA-binding domain of human CPEB3. The two predicted residues, F430 and F474, were experimentally verified to bind RNA, in particular F430, whose mutation to alanine or asparagine nearly abolished RNA binding. The method has been implemented in a webserver called DR_bind1, which is freely available with no login requirement at http://drbind.limlab.ibms.sinica.edu.tw.

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Section: Resultsmentioning

confidence: 99%

Identifying RNA-binding residues based on evolutionary conserved structural and energetic features

Chen

Sargsyan

Wright

et al. 2013

Nucleic Acids Research

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“…The CPEB3 monoclonal antibody has been described before (Chao et al, 2012; Wang and Huang, 2012). Alexa Fluor-conjugated secondary antibodies were obtained from Invitrogen.…”

Section: Methodsmentioning

confidence: 99%

Elevated activation of CaMKIIÎ± in the CPEB3-knockout hippocampus impairs a specific form of NMDAR-dependent synaptic depotentiation

Huang

Chao

Tsai

et al. 2014

Front. Cell. Neurosci.

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Cytoplasmic polyadenylation element binding protein 3 (CPEB3) is a sequence-specific RNA-binding protein that confines the strength of glutamatergic synapses by translationally downregulating the expression of multiple plasticity-related proteins (PRPs), including the N-methyl-D-aspartate receptor (NMDAR) and the postsynaptic density protein 95 (PSD95). CPEB3 knockout (KO) mice exhibit hippocampus-dependent abnormalities related not only to long-term spatial memory but also to the short-term acquisition and extinction of contextual fear memory. In this study, we identified a specific form of NMDAR-dependent synaptic depotentiation (DPT) that is impaired in the adult CPEB3 KO hippocampus. In parallel, cultured KO neurons also exhibited delayed morphological and biochemical responses under NMDA-induced chemical long-term depression (c-LTD). The c-LTD defects in the KO neurons include elevated activation of calcium/calmodulin-dependent protein kinase II alpha subunit (CaMKIIα), increased Ser831 phosphorylation of GluA1 and slow degradation of PSD95 and GluA1. Because transient pharmacological suppression of CaMKIIα activity during the DPT-initiating phase successfully reversed the LTP in the KO hippocampus, DPT and c-LTD in the two different systems shared common molecular defects due to the absence of CPEB3. Together, our results suggest that CPEB3 deficiency imbalances NMDAR-activated CaMKIIα signaling, which consequently fails to depress synaptic strength under certain stimulation conditions.

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“…Such membrane-tonucleus signaling mechanism would be similar to Neogenin and DCC, two neuronal CAMs that are closely related to vertebrate DSCAMs and cleaved by proteases resulting in the release of C-terminal ICD fragments, which then translocate into the nucleus where they regulate gene transcription (Taniguchi et al, 2003;Goldschneider et al, 2008). IPO5 is an importin beta mediating nuclear protein import (Yaseen & Blobel, 1997) and can directly interact with the nuclear localization signal (NLS) of its cargo (Chao et al, 2012). We therefore considered that the ICDs of DSCAMs might contain an NLS serving as docking site for IPO5.…”

Section: Usp21mentioning

confidence: 99%

Nuclear import of the DSCAM ‐cytoplasmic domain drives signaling capable of inhibiting synapse formation

et al. 2019

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DSCAM and DSCAML1 are immunoglobulin and cell adhesion‐type receptors serving important neurodevelopmental functions including control of axon growth, branching, neurite self‐avoidance, and neuronal cell death. The signal transduction mechanisms or effectors of DSCAM receptors, however, remain poorly characterized. We used a human ORFeome library to perform a high‐throughput screen in mammalian cells and identified novel cytoplasmic signaling effector candidates including the Down syndrome kinase Dyrk1a, STAT3, USP21, and SH2D2A. Unexpectedly, we also found that the intracellular domains (ICDs) of DSCAM and DSCAML1 specifically and directly interact with IPO5, a nuclear import protein of the importin beta family, via a conserved nuclear localization signal. The DSCAM ICD is released by γ‐secretase‐dependent cleavage, and both the DSCAM and DSCAML1 ICDs efficiently translocate to the nucleus. Furthermore, RNA sequencing confirms that expression of the DSCAM as well as the DSCAML1 ICDs alone can profoundly alter the expression of genes associated with neuronal differentiation and apoptosis, as well as synapse formation and function. Gain‐of‐function experiments using primary cortical neurons show that increasing the levels of either the DSCAM or the DSCAML1 ICD leads to an impairment of neurite growth. Strikingly, increased expression of either full‐length DSCAM or the DSCAM ICD, but not the DSCAML1 ICD, significantly decreases synapse numbers in primary hippocampal neurons. Taken together, we identified a novel membrane‐to‐nucleus signaling mechanism by which DSCAM receptors can alter the expression of regulators of neuronal differentiation and synapse formation and function. Considering that chromosomal duplications lead to increased DSCAM expression in trisomy 21, our findings may help uncover novel mechanisms contributing to intellectual disability in Down syndrome.

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NMDAR signaling facilitates the IPO5-mediated nuclear import of CPEB3

Cited by 48 publications

References 43 publications

Identifying RNA-binding residues based on evolutionary conserved structural and energetic features

Identifying RNA-binding residues based on evolutionary conserved structural and energetic features

Elevated activation of CaMKIIÎ± in the CPEB3-knockout hippocampus impairs a specific form of NMDAR-dependent synaptic depotentiation

Nuclear import of the DSCAM ‐cytoplasmic domain drives signaling capable of inhibiting synapse formation

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