Functional dissection of RanBP2 and Nup88/Nup214 subcomplex in nucleocytoplasmic transport
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE133177 | GEO | 2020/06/15
REPOSITORIES: GEO
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Project description:Functional dissection of RanBP2 and Nup88/Nup214 subcomplex in nucleocytoplasmic transport
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Project description:Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example is contact with the endoplasmic reticulum at mitochondrial-associated ER membranes (MAMs), which control pathways including redox and calcium homeostasis. Recent studies also reported direct mitochondria–nuclear membrane contacts in cancer cells and yeast that promote pro-survival signaling, but how exchange occurs across two largely impermeable membranes remains unclear. Here, we describe the existence of direct interactions between the nuclear pore and the mitochondria. In two unbiased proteomic screens, GST pulldown and BioID, VDAC1 was the top mitochondrial candidate that interacts with the nuclear pore protein RANBP2. In vitro RANBP2 CRISPR knock-out, RANBP2 truncation, or site directed mutagenesis of RANBP2-interacting amino acids in VDAC1 resulted in reduced mitochondria-nucleus proximity and decreased nuclear ATP and phosphocreatine levels. This was accompanied by a decline in levels of the nuclear phosphoproteome, and downregulation of pathways involved in histone modification, cellular differentiation and transcriptional regulation in vitro. We show differential ATAC peaks in Ranbp2 Wildtype and knockout cells in 10T1/2. Moreover, deletion of RANBP2 C-terminal domain in vivo in mice resulted in embryonic lethality due to cardiac and neural crest differentiation defects. Collectively, these results describe a mechanism by which mitochondria directly interact with the NPC, a phenomenon which is critical for regulation nuclear energetics and cellular differentiation during embryonic development.
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Project description:Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example is contact with the endoplasmic reticulum at mitochondrial-associated ER membranes (MAMs), which control pathways including redox and calcium homeostasis. Recent studies also reported direct mitochondria–nuclear membrane contacts in cancer cells and yeast that promote pro-survival signaling, but how exchange occurs across two largely impermeable membranes remains unclear. Here, we describe the existence of direct interactions between the nuclear pore and the mitochondria. In two unbiased proteomic screens, GST pulldown and BioID, VDAC1 was the top mitochondrial candidate that interacts with the nuclear pore protein RANBP2. In vitro RANBP2 CRISPR knock-out, RANBP2 truncation, or site directed mutagenesis of RANBP2-interacting amino acids in VDAC1 resulted in reduced mitochondria-nucleus proximity and decreased nuclear ATP and phosphocreatine levels. This was accompanied by a decline in levels of the nuclear phosphoproteome, and downregulation of pathways involved in histone modification, cellular differentiation and transcriptional regulation in vitro. We show differential H3K27me3 histone epigenetic landscape in Ranbp2 Wildtype and knockout cells in 10T1/2. Moreover, deletion of RANBP2 C-terminal domain in vivo in mice resulted in embryonic lethality due to cardiac and neural crest differentiation defects. Collectively, these results describe a mechanism by which mitochondria directly interact with the NPC, a phenomenon which is critical for regulation nuclear energetics and cellular differentiation during embryonic development.
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Project description:Activation of the transforming growth factor β (TGF-β) signaling leads to established hallmarks of cancer such as the epithelial-to-mesenchymal transition (EMT), initiating cancer dissemination and increasing chemoresistance. TGF-β signal by binding to its type I and II receptors, leading to parallel activation of SMAD proteins, ubiquitin ligases and protein kinases. Here, using a panel of tumor cells we show that TGF-β activation induces the expression of the mammalian nuclear long non-coding RNA (lncRNA) VIM-AS1 (Vimentin antisense RNA 1) variant 2 (v.2) via the formation of a complex among the transcriptional factors GATA6-SMAD-SPI1. Furthermore, transcriptomic analysis indicated VIM-AS1 enhancing TGF-β signaling and EMT, as further validated by functional gain or loss assays. Mechanistically, the TGF-β-induced VIM-AS1 v.2 enhanced SMAD nucleocytoplasmic shuttling by interacting with the N-terminus domain of the nucleoporin RanBP2 (Nup358), whereby acting as a scaffold molecule, facilitates the binding of RanBP2 with SMAD2/3 and its further nuclear import. Finally, VIM-AS1 increases invasion and motility of tumor cells and emerges as a promising therapeutic target to sensitize cancer cells to chemotherapeutic drugs. Hence, we delineated a novel signaling mechanism for VIM-AS1 v.2 facilitating TGF-β response in tumor cells via SMAD nucleocytoplasmic shuttling.
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