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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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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

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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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Transportin-1 (TRN-1) orchestrates HIV-1 uncoating and nuclear import

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Mechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP

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SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic that is a serious global health threat. Evasion of interferon-mediated antiviral signaling is a common defense strategy that pathogenic viruses use to replicate and propagate in their host. In this study, we show that SARS-CoV-2 is able to efficiently block STAT1 and STAT2 nuclear translocation in order to impair transcriptional induction of interferon (IFN) stimulated genes (ISGs). Our results demonstrate that the viral accessory protein Orf6 exerts this anti-IFN activity. We found that SARS-CoV-2 Orf6 localizes at the nuclear pore complex (NPC) where it directly interacts with Nup98-Rae1 via its C-terminal domain to impair docking of cargo-receptor complexes and disrupt nuclear import functions. In addition, we show that a methionine-to-arginine substitution at residue 58 impairs Orf6 binding to the Nup98-Rae1 complex and abolishes its IFN antagonistic function. All together our data unravel a new mechanism of viral antagonism in which a virus hijacks the Nup98-Rae1 complex to overcome the antiviral action of IFN.

2020-10-20 | GSE159593 | GEO

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