Cul4 ubiquitin ligase cofactor DCAF12 promotes neurotransmitter release and homeostatic plasticity

Patrón, Lilian A.; Nagatomo, Kei; Eves, David Tyler; Imad, Mays; Young, Kimberly; Torvund, Meaghan; Guo, Xiufang; Rogers, Gerald S.; Zinsmaier, Konrad E.

doi:10.1083/jcb.201805099

Cited by 16 publications

(11 citation statements)

References 77 publications

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“…In contrast, CRL4 DCAF12 did not promote the ubiquitination of the membrane-tethered Yki (Myr-Myc-Yki; Fig. 5R), consistent with a previous finding DCAF12 forms a nuclear complex with Cul4 and thus targets nuclear proteins for ubiquitination and degradation (Patrón et al 2019). CRL4 DCAF12 -mediated Myc-Yki ubiquitination was inhibited by coexpression of CDK7 or by the S169D mutation but increased by the S169A mutation or by CDK7 RNAi (Fig.…”

Section: Because the Proteasome Inhibitor Mg132 Could Stabilizesupporting

confidence: 92%

CDK7 regulates organ size and tumor growth by safeguarding the Hippo pathway effector Yki/Yap/Taz in the nucleus

Cho

Wang

et al. 2019

Genes Dev.

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Hippo signaling controls organ size and tumor progression through a conserved pathway leading to nuclear translocation of the transcriptional effector Yki/Yap/Taz. Most of our understanding of Hippo signaling pertains to its cytoplasmic regulation, but how the pathway is controlled in the nucleus remains poorly understood. Here we uncover an evolutionarily conserved mechanism by which CDK7 promotes Yki/Yap/Taz stabilization in the nucleus to sustain Hippo pathway outputs. We found that a modular E3 ubiquitin ligase complex CRL4DCAF12 binds and targets Yki/Yap/Taz for ubiquitination and degradation, whereas CDK7 phosphorylates Yki/Yap/Taz at S169/S128/S90 to inhibit CRL4DCAF12 recruitment, leading to Yki/Yap/Taz stabilization. As a consequence, inactivation of CDK7 reduced organ size and inhibited tumor growth, which could be reversed by restoring Yki/Yap activity. Our study identifies an unanticipated layer of Hippo pathway regulation, defines a novel mechanism by which CDK7 regulates tissue growth, and implies CDK7 as a drug target for Yap/Taz-driven cancer.

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Section: Because the Proteasome Inhibitor Mg132 Could Stabilizesupporting

confidence: 92%

CDK7 regulates organ size and tumor growth by safeguarding the Hippo pathway effector Yki/Yap/Taz in the nucleus

Cho

Wang

et al. 2019

Genes Dev.

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“…Lastly, FER plays a role in neuronal cell death after brain damage ( Lee et al, 2008 ). The only gene down-regulated by P301L tau is DCAF12 , which is a component of the Cullin-RING ubiquitin ligase complex ( Patrón et al, 2019 ). This gene is also down-regulated by WT tau and belongs to genes associated with ubiquitinization processes.…”

Section: Resultsmentioning

confidence: 99%

Tau Modulates mRNA Transcription, Alternative Polyadenylation Profiles of hnRNPs, Chromatin Remodeling and Spliceosome Complexes

Montalbano

Jaworski

Garcia

et al. 2021

Front. Mol. Neurosci.

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Tau protein is a known contributor in several neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). It is well-established that tau forms pathological aggregates and fibrils in these diseases. Tau has been observed within the nuclei of neurons, but there is a gap in understanding regarding the mechanism by which tau modulates transcription. We are interested in the P301L mutation of tau, which has been associated with FTD and increased tau aggregation. Our study utilized tau-inducible HEK (iHEK) cells to reveal that WT and P301L tau distinctively alter the transcription and alternative polyadenylation (APA) profiles of numerous nuclear precursors mRNAs, which then translate to form proteins involved in chromatin remodeling and splicing. We isolated total mRNA before and after over-expressing tau and then performed Poly(A)-ClickSeq (PAC-Seq) to characterize mRNA expression and APA profiles. We characterized changes in Gene Ontology (GO) pathways using EnrichR and Gene Set Enrichment Analysis (GSEA). We observed that P301L tau up-regulates genes associated with reactive oxygen species responsiveness as well as genes involved in dendrite, microtubule, and nuclear body/speckle formation. The number of genes regulated by WT tau is greater than the mutant form, which indicates that the P301L mutation causes loss-of-function at the transcriptional level. WT tau up-regulates genes contributing to cytoskeleton-dependent intracellular transport, microglial activation, microtubule and nuclear chromatin organization, formation of nuclear bodies and speckles. Interestingly, both WT and P301L tau commonly down-regulate genes responsible for ubiquitin-proteosome system. In addition, WT tau significantly down-regulates several genes implicated in chromatin remodeling and nucleosome organization. Although there are limitations inherent to the model systems used, this study will improve understanding regarding the nuclear impact of tau at the transcriptional and post-transcriptional level. This study also illustrates the potential impact of P301L tau on the human brain genome during early phases of pathogenesis.

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“…Lastly, FER plays a role in neuronal cell death after brain damage 49 . The only gene down-regulated by P301L tau is DCAF12 , which is a component of the Cullin-RING ubiquitin ligase complex 50 . This gene is also down-regulatated by WT tau and belongs to genes associated with ubiquitinization processes.…”

Section: Resultsmentioning

confidence: 99%

Tau modulates mRNA transcription, alternative polyadenylation profiles of hnRNPs, chromatin remodeling and spliceosome complexes

Montalbano

Jaworski

Garcia

et al. 2021

Preprint

View full text Add to dashboard Cite

Tau protein is a known contributor in several neurodegenerative diseases, including Alzheimer ’s disease (AD) and frontotemporal dementia (FTD). It is well-established that tau forms pathological aggregates and fibrils in these diseases. Tau has been observed within the nuclei of neurons, but there is a gap in understanding regarding the mechanism by which tau modulates transcription. We are interested in the P301L mutation of tau, which has been associated with FTD and increased tau aggregation. Our study utilized tau-inducible HEK (iHEK) cells to reveal that WT and P301L tau distinctively alter the transcription and alternative polyadenylation (APA) profiles of numerous nuclear precursors mRNAs, which then translate to form proteins involved in chromatin remodeling and splicing. We isolated total mRNA before and after over-expressing tau and then performed Poly(A)-ClickSeq (PAC-Seq) to characterize mRNA expression and APA profiles. We characterized changes in Gene Ontology (GO) pathways using EnrichR and Gene Set Enrichment Analysis (GSEA). We observed that P301L tau up-regulates genes associated with reactive oxygen species responsiveness as well as genes involved in dendrite, microtubule, and nuclear body/speckle formation. The number of genes regulated by WT tau is greater than the mutant form, which indicates that the P301L mutation causes loss-of-function at the transcriptional level. WT tau up-regulates genes contributing to cytoskeleton-dependent intracellular transport, microglial activation, microtubule and nuclear chromatin organization, formation of nuclear bodies and speckles. Interestingly, both WT and P301L tau commonly down-regulate genes responsible for ubiquitin-proteosome system. In addition, WT tau significantly down-regulates several genes implicated in chromatin remodeling and nucleosome organization. Although there are limitations inherent to the model systems used, this study will improve understanding regarding the nuclear impact of tau at the transcriptional and post-transcriptional level. This study also illustrates the potential impact of P301L tau on the human brain genome during early phases of pathogenesis.

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Cul4 ubiquitin ligase cofactor DCAF12 promotes neurotransmitter release and homeostatic plasticity

Cited by 16 publications

References 77 publications

CDK7 regulates organ size and tumor growth by safeguarding the Hippo pathway effector Yki/Yap/Taz in the nucleus

CDK7 regulates organ size and tumor growth by safeguarding the Hippo pathway effector Yki/Yap/Taz in the nucleus

Tau Modulates mRNA Transcription, Alternative Polyadenylation Profiles of hnRNPs, Chromatin Remodeling and Spliceosome Complexes

Tau modulates mRNA transcription, alternative polyadenylation profiles of hnRNPs, chromatin remodeling and spliceosome complexes

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