Post-translational Membrane Insertion of Tail-anchored Transmembrane EF-hand Ca2+ Sensor Calneurons Requires the TRC40/Asna1 Protein Chaperone

Hradsky, Johannes; Raghuram, Vijeta; Reddy, Parameshwar Pasham; Navarro, Gemma; Hupe, Mike; Casadó, Vicent; McCormick, Peter J.; Sharma, Yogendra; Kreutz, Michael R.; Mikhaylova, Marina

doi:10.1074/jbc.m111.280339

Cited by 27 publications

(43 citation statements)

References 54 publications

(82 reference statements)

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“…This gene is an EF-hand calcium sensor protein with high expression in the hippocampus and cerebral cortex, which are two of the brain regions most implicated in schizophrenia [15,16]. Previous studies have reported that CALN1 negatively regulates Golgi-to-plasma membrane trafficking by inhibiting the activity of phosphatidylinositol 4-OH kinase III (PI-4Kβ) [16,17], and it is presumed to be involved in a calcium signaling pathway. Interestingly, a recent genome-wide association analysis that identified 13 new risk loci for schizophrenia suggested the involvement of neuronal calcium signaling in the etiology of schizophrenia [6].…”

Section: Discussionmentioning

confidence: 97%

Experimental validation of candidate schizophrenia gene CALN1 as a target for microRNA-137

Xia

Zhou

Wang

et al. 2015

Neuroscience Letters

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Section: Discussionmentioning

confidence: 97%

Experimental validation of candidate schizophrenia gene CALN1 as a target for microRNA-137

Xia

Zhou

Wang

et al. 2015

Neuroscience Letters

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“…Nevertheless, for Sec61β as well as for emerin, the signals were specific and almost exclusively detected in the cytoplasmic region of the cells, consistent with interactions occurring at or close to ER membranes. PLAs have been used previously for the detection of TRC40 binding to tail-anchored proteins (Hradsky et al, 2011), but, to our knowledge, only upon overexpression of both interacting partners. Here, we used antibodies against endogenous emerin to monitor binding to lamin A/C as well as Myc-tagged TRC40.…”

Section: Discussionmentioning

confidence: 99%

Emery–Dreifuss muscular dystrophy mutations impair TRC40-mediated targeting of emerin to the inner nuclear membrane

Pfaff

Rivera‐Monroy

Jamieson

et al. 2016

Journal of Cell Science

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Emerin is a tail-anchored protein that is found predominantly at the inner nuclear membrane (INM), where it associates with components of the nuclear lamina. Mutations in the emerin gene cause EmeryDreifuss muscular dystrophy (EDMD), an X-linked recessive disease. Here, we report that the TRC40/GET pathway for post-translational insertion of tail-anchored proteins into membranes is involved in emerin-trafficking. Using proximity ligation assays, we show that emerin interacts with TRC40 in situ. Emerin expressed in bacteria or in a cell-free lysate was inserted into microsomal membranes in an ATP-and TRC40-dependent manner. Dominant-negative fragments of the TRC40-receptor proteins WRB and CAML (also known as CAMLG) inhibited membrane insertion. A rapamycin-based dimerization assay revealed correct transport of wild-type emerin to the INM, whereas TRC40-binding, membrane integration and INMtargeting of emerin mutant proteins that occur in EDMD was disturbed. Our results suggest that the mode of membrane integration contributes to correct targeting of emerin to the INM.

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“…S4). Calnl is a brain-specific calcium-binding protein that regulates Golgi-to-plasma membrane trafficking of vesicles (24; 25) and under certain conditions is reported to alter D2-A2AR heteromerization (26). The predicted Calnl -fragment is located 1,524 kb away from the Auts2 bait.…”

Section: Resultsmentioning

confidence: 99%

Cocaine-Induced Chromatin Modifications Associate With Increased Expression and Three-Dimensional Looping of Auts2

Engmann

Labonté

Mitchell

et al. 2017

Biological Psychiatry

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Background Exposure to drugs of abuse alters the epigenetic landscape of the brain’s reward regions such as the nucleus accumbens (NAc). We investigated how combinations of chromatin modifications affect genes that regulate responses to cocaine. We focused on autism-candidate 2 (Auts2), a gene linked to human evolution and cognitive disorders, which displays strong clustering of cocaine-induced chromatin modifications in this brain region. Methods We combined chromosome conformation capture (4C and 3C) and related approaches with behavioral paradigms relevant to cocaine phenotypes. Cell type-specific functions were assessed by FACS-sorting and viral-mediated overexpression in Cre-dependent mouse lines. Results We observed that Auts2 gene expression is increased by repeated cocaine administration specifically in D2-type medium spiny neurons (MSNs) in NAc, an effect seen in male but not female mice. Auts2 mRNA expression was also upregulated postmortem in NAc of male human cocaine addicts. We obtained evidence that chromosomal looping, bypassing 1,524 kb of linear genome, connects Auts2 to the calneuron 1 (Caln1) gene locus under baseline conditions. This looping was disrupted after repeated cocaine exposure, resulting in increased expression of both genes in D2 MSNs. Cocaine exposure reduces binding of CTCF, a chromosomal scaffolding protein, and increases histone and DNA methylation, at the Auts-Caln1 loop base in NAc. Cell type-specific overexpression of Auts2 or Calnl in D2 MSNs demonstrated that both genes promote cocaine reward. Conclusions These findings suggest that cocaine-induced alterations of neuronal 3D genome organization destabilize higher order chromatin at specific loci that regulate responses to the drug.

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Post-translational Membrane Insertion of Tail-anchored Transmembrane EF-hand Ca2+ Sensor Calneurons Requires the TRC40/Asna1 Protein Chaperone

Cited by 27 publications

References 54 publications

Experimental validation of candidate schizophrenia gene CALN1 as a target for microRNA-137

Experimental validation of candidate schizophrenia gene CALN1 as a target for microRNA-137

Emery–Dreifuss muscular dystrophy mutations impair TRC40-mediated targeting of emerin to the inner nuclear membrane

Cocaine-Induced Chromatin Modifications Associate With Increased Expression and Three-Dimensional Looping of Auts2

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