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AKIRIN2 controls the nuclear import of proteasomes in vertebrates

ABSTRACT: AKIRIN2 controls the nuclear import of proteasomes in vertebrates

PROVIDER: PRJNA662348 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12610272.fastq.gz	Fastqsanger.gz
	SRR12610273.fastq.gz	Fastqsanger.gz
	SRR12610274.fastq.gz	Fastqsanger.gz
	SRR12610275.fastq.gz	Fastqsanger.gz
	SRR12610276.fastq.gz	Fastqsanger.gz

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AKIRIN2 controls the nuclear import of proteasomes in vertebrates

Project description:Protein expression and turnover are controlled through a complex interplay of transcriptional, post-transcriptional and post-translational mechanisms to enable spatial and temporal regulation of cellular processes. To systematically elucidate such gene regulatory networks, we developed a CRISPR screening assay based on time-controlled Cas9 mutagenesis, intracellular immunostaining and fluorescence-activated cell sorting that enables the identification of regulatory factors independent of their effects on cellular fitness. We pioneered this approach by systematically probing the regulation of the transcription factor MYC, a master regulator of cell growth. Our screens uncover a highly conserved protein, AKIRIN2, that is essentially required for nuclear protein degradation. We found that AKIRIN2 forms homodimers that directly bind to fully assembled 20S proteasomes to mediate their nuclear import. During mitosis, proteasomes are excluded from condensing chromatin and re-imported into newly formed daughter nuclei in a highly dynamic, AKIRIN2-dependent process. Cells undergoing mitosis in the absence of AKIRIN2 become devoid of nuclear proteasomes, rapidly causing accumulation of MYC and other nuclear proteins. Collectively, our study reveals a dedicated pathway controlling the nuclear import of proteasomes in vertebrates and establishes a scalable approach to decipher regulators in essential cellular processes.

2021-08-27 | GSE157663 | GEO

AKIRIN2 controls the nuclear import of proteasomes in vertebrates

Project description:AKIRIN2 regulates the import of proteasomes into the nucleus. To analyze AKIRIN2-containing proteasome complexes, we performed co-immunoprecipitation of GST-tagged AKIRIN2, followed by sucrose gradient centrifugation and mass spectrometry.

2021-11-02 | PXD027343 | Pride

AKIRIN2 controls the nuclear import of proteasomes in vertebrates

Project description:AKIRIN2 is an essential negative regulator of nuclear protein, including oncogenic transcription factors such as MYC. To identify the mode of AKIRIN2-dependent nuclear protein regulation we performed pulldown and mass spectrometry of V5-tagged AKIRIN2 variants or nuclear GFP control.

2021-11-02 | PXD027184 | Pride

Transcriptomic analysis of mutant yeast strains deficient in Xrn1 nuclear import

Project description:The goal of the project was to study the transcription rates and mRNA levels, genome-wide, in several mutants in Xrn1 defetive in nuclear import. We used Genomic Run-On (GRO) experiment in wild type and xrn1 mutant strains.

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A conserved notochord enhancer controls pancreas development in vertebrates

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Lower nuclear pore numbers in cardiomyocytes decrease nuclear import of signaling proteins, which restricts adaptive gene regulation, and improves cardiac stress response in vivo

Project description:Nuclear pores are essential pathways for nuclear-cytoplasmic transport of molecules. Whether and how cells change nuclear pores to alter nuclear transport and cellular function is unknown. Here, we show that heart muscle cells (cardiomyocytes) undergo a 63% decrease in nuclear pore numbers during differentiation, which alters their response to extracellular signals. This maturation-associated decline in nuclear pore numbers per nucleus is associated with lower nuclear levels and import of Mitogen-activated Protein Kinase (MAPK) signaling proteins. Experimental reduction of nuclear pore numbers decreased nuclear import of MAPK signaling proteins. In a mouse model of high blood pressure, reduction of cardiomyocyte nuclear pore numbers reduced adverse heart remodeling and gene regulation, which reduced progression to lethal heart failure. The observed decrease in nuclear pore numbers in cardiomyocyte differentiation and resulting functional changes suggest a paradigm by which terminally differentiated cells could permanently alter their handling of information flux across the nuclear envelope and, with that, their behavior.

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Lipid-anchored Proteasomes Control Membrane Protein Homeostasis

Project description:As the major protein degradation machinery of eukaryotic cells, the 26S proteasome is generally thought to localize in the nucleus and cytosol. A portion of proteasomes are known to associate with various membrane structures of the cell, the mechanism and biological meaning of which have been elusive. Here we show that N-myristoylation of the proteasome subunit Rpt2 is an evolutionarily conserved determinant of proteasome-membrane interaction. Loss of this modification leads to embryonic lethality in mice, significant reduction of migration ability in MEFs and profound changes in the membrane-associated proteome as determined by SILAC-MS, suggesting a key role of membrane-tethered proteasomes in carrying out compartmentalized protein degradation. And the tumorigenicity is reduced in the oncogene-transformed MEF without modification. Serendipitously, we found that the Rpt2-G2A mutation cell lines confers partial resistance to proteasome inhibitors, such as Bortezomib and MG132. Thus, N-myristoylation of Rpt2 determines the localization and activity of the proteasome at the membrane, which is critical for embryogenesis, cellular homeostasis and tumorigenesis.

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Lipid-anchored Proteasomes Control Membrane Protein Homeostasis

Project description:Lipid-anchored Proteasomes Control Membrane Protein Homeostasis

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