GEMIN4 functions as a coregulator of the mineralocorticoid receptor

Yang, Jun; Fuller, Peter J.; Morgan, James J.; Shibata, Hirotaka; Clyne, Colin; Young, Morag J.

doi:10.1530/jme-14-0078

Cited by 22 publications

(9 citation statements)

References 68 publications

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“…Gemin4 (Gem4) is tethered to the SMN complex via direct binding to Gem3 (CHARROUX et al 2000;MEISTER et al 2000). Gem4 has been implicated in nuclear receptor binding (DI et al 2003;YANG et al 2015), microRNA biology (HUTVÁGNER AND ZAMORE 2002;MEISTER et al 2005) and in nuclear import of the SMN complex (NARAYANAN et al 2004;MEIER et al 2018). In human cell lysates, SMN and Gemins2-4 are thought to be essential for proper assembly of the Sm core (SHPARGEL AND MATERA 2005).…”

Section: Introductionmentioning

confidence: 99%

Composition of the Survival Motor Neuron (SMN) complex in Drosophila melanogaster

Matera

Raimer

Schmidt

et al. 2018

Preprint

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Spinal Muscular Atrophy (SMA) is caused by homozygous mutations in the human survival motor neuron 1 (SMN1) gene. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. SMN is part of an oligomeric complex with core binding partners, collectively called Gemins. Biochemical and cell biological studies demonstrate that certain Gemins are required for proper snRNP assembly and transport. However, the precise functions of most Gemins are unknown. To gain a deeper understanding of the SMN complex in the context of metazoan evolution, we investigated the composition of the SMN complex in Drosophila melanogaster. Using a stable transgenic line that exclusively expresses Flag-tagged SMN from its native promoter, we previously found that Gemin2, Gemin3, Gemin5, and all nine classical Sm proteins, including Lsm10 and Lsm11, co-purify with SMN. Here, we show that CG2941 is also highly enriched in the pulldown. Reciprocal co-immunoprecipitation reveals that epitope-tagged CG2941 interacts with endogenous SMN in Schneider2 cells. Bioinformatic comparisons show that CG2941 shares sequence and structural similarity with metazoan Gemin4.Additional analysis shows that three other genes (CG14164, CG31950 and CG2371) are not orthologous to Gemins 6-7-8, respectively, as previously suggested. In D.melanogaster, CG2941 is located within an evolutionarily recent genomic triplication with two other nearly identical paralogous genes (CG32783 and CG32786). RNAimediated knockdown of CG2941 and its two close paralogs reveals that Gemin4 is essential for organismal viability.

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Section: Introductionmentioning

confidence: 99%

Composition of the Survival Motor Neuron (SMN) complex in Drosophila melanogaster

Matera

Raimer

Schmidt

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Gemin4 is tethered to the SMN complex via direct binding to Gemin3 (Charroux et al 2000; Meister et al 2000). Gemin4 has been implicated in nuclear receptor binding (Di et al 2003; Yang et al 2015), microRNA biology (Hutvágner and Zamore 2002; Meister et al 2005) and in nuclear import of the SMN complex (Narayanan et al 2004; Meier et al 2018). In human cell lysates, SMN and Gemins2-4 are thought to be essential for proper assembly of the Sm core (Shpargel and Matera 2005).…”

mentioning

confidence: 99%

Composition of the Survival Motor Neuron (SMN) Complex in Drosophila melanogaster

Matera

Raimer²,

Schmidt³

et al. 2019

G3 Genes|Genomes|Genetics

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Spinal Muscular Atrophy (SMA) is caused by homozygous mutations in the human survival motor neuron 1 ( SMN1 ) gene. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. SMN is part of an oligomeric complex with core binding partners, collectively called Gemins. Biochemical and cell biological studies demonstrate that certain Gemins are required for proper snRNP assembly and transport. However, the precise functions of most Gemins are unknown. To gain a deeper understanding of the SMN complex in the context of metazoan evolution, we investigated its composition in Drosophila melanogaster . Using transgenic flies that exclusively express Flag-tagged SMN from its native promoter, we previously found that Gemin2, Gemin3, Gemin5, and all nine classical Sm proteins, including Lsm10 and Lsm11, co-purify with SMN. Here, we show that CG2941 is also highly enriched in the pulldown. Reciprocal co-immunoprecipitation reveals that epitope-tagged CG2941 interacts with endogenous SMN in Schneider2 cells. Bioinformatic comparisons show that CG2941 shares sequence and structural similarity with metazoan Gemin4. Additional analysis shows that three other genes ( CG14164 , CG31950 and CG2371 ) are not orthologous to Gemins 6-7-8, respectively, as previously suggested. In D.melanogaster , CG2941 is located within an evolutionarily recent genomic triplication with two other nearly identical paralogous genes ( CG32783 and CG32786 ). RNAi-mediated knockdown of CG2941 and its two close paralogs reveals that Gemin4 is essential for organismal viability.

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“…The Gem (nuclear organelle)-associated protein 4 (GEMIN4) and nuclear transcription factor Y subunit gamma (NF-YC) act as MR corepressors in an agonist-dependent manner (26, 27), whereas Ubiquitin-Conjugating Enzyme E2I (Ubc9), SRC-1, and PGC1 α significantly increase MR activation in COS-7 and HEK293 cells (25, 28). Our findings now add RACK1 to the list of MR coactivators.…”

Section: Discussionmentioning

confidence: 99%

Interaction of the Mineralocorticoid Receptor With RACK1 and Its Role in Aldosterone Signaling

et al. 2017

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The mineralocorticoid receptor (MR) is a member of the steroid-thyroid hormone receptor superfamily of ligand-dependent transcription factors with diverse functions including the biological actions of aldosterone. Identification of the various transcriptional coregulators of MR is essential for understanding the complexity of MR signaling pathways under physiological and pathological conditions. We used a yeast two-hybrid system to find proteins that interact with a full-length MR and found, among other proteins, that MR interacted specifically with receptor for activated C kinase 1 (RACK1), a scaffolding protein. Overexpression of RACK1 using a tetracycline-inducible lentivirus in mouse cortical collecting duct M1 cells stably expressing the rat MR and a Gaussia luciferase gene reporter under a hormone-response element promoter resulted in enhanced agonist-dependent MR transactivation. Knockdown of RACK1 protein expression by short hairpin RNAs led to a significant reduction in MR activation of the reporter gene and the endogenous genes Ctla2α and Psca. We also demonstrated that RACK1 regulation of MR action is mediated through phosphorylation by the PKC-β signaling pathway. MR and RACK1 were coimmunoprecipitated using an MR antibody in male Sprague-Dawley brain tissue and M1-rMR cells, and colocalization in M1-rMR cells and male rat brains was confirmed by immunofluorescence and immunohistochemistry. The scaffolding protein RACK1 is associated with MR under basal and agonist-stimulated conditions and facilitates agonist-stimulated MR actions through PKC-β. These findings indicate that RACK1 is a newly described coactivator of MR.

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GEMIN4 functions as a coregulator of the mineralocorticoid receptor

Cited by 22 publications

References 68 publications

Composition of the Survival Motor Neuron (SMN) complex in Drosophila melanogaster

Composition of the Survival Motor Neuron (SMN) complex in Drosophila melanogaster

Composition of the Survival Motor Neuron (SMN) Complex in Drosophila melanogaster

Interaction of the Mineralocorticoid Receptor With RACK1 and Its Role in Aldosterone Signaling

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