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Protein homeostasis is maintained by proteasomes containing PSMB9 induced by EEF1A2 upon mitochondrial stress

ABSTRACT: Protein homeostasis is maintained by proteasomes containing PSMB9 induced by EEF1A2 upon mitochondrial stress

PROVIDER: PRJNA803200 | ENA |

REPOSITORIES: ENA

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Protein homeostasis is maintained by proteasomes containing PSMB9 induced by EEF1A2 upon mitochondrial stress

Project description:Perturbed proteostasis and mitochondrial dysfunction are often associated with age-related diseases such as Alzheimer’s and Parkinson’s diseases. However, the link between them remains incompletely understood. Mitochondrial dysfunction causes proteostasis imbalance, and cells respond to restore proteostasis by increasing proteasome activity and molecular chaperons in yeast and C. elegans. Here, we demonstrate the presence of similar responses in humans. Mitochondrial dysfunction upregulates a small heat shock protein HSPB1 and an immunoproteasome subunit PSMB9 leading to an increase in proteasome activity. HSPB1 and PSMB9 are required to prevent protein aggregation upon mitochondrial dysfunction. Moreover, PSMB9 expression is dependent on a translation elongation factor EEF1A2, and PSMB9-containing proteasomes are located near mitochondria, enabling fast local degradation of aberrant proteins. Our findings put a step forward in understanding the stress response triggered by mitochondrial dysfunction, and may be useful for therapeutic strategies to prevent or delay the onset of age-related diseases and attenuate their progression.

2023-07-04 | PXD031282 | Pride

Protein homeostasis is maintained by proteasomes containing PSMB9 induced by EEF1A2 upon mitochondrial stress

2023-07-03 | PXD031374 | Pride

Protein homeostasis is maintained by proteasomes containing PSMB9 induced by EEF1A2 upon mitochondrial stress

Project description:Analysis of global gene expression changes in HEK293T cells triggered by mutations in NDUFA11 and NDUFA13 genes

2023-05-31 | GSE196068 | GEO

Lipid-anchored Proteasomes Control Membrane Protein Homeostasis

Project description:Lipid-anchored Proteasomes Control Membrane Protein Homeostasis

| PRJNA971586 | ENA

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.

2023-05-16 | GSE232308 | GEO

A cell-based platform for the investigation of immunoproteasome subunit β5i expression and biology of β5i-containing proteasomes

Project description:The degradation of intracellular proteins is a dynamic and tightly regulated process. Most of such substrates is hydrolyzed by proteasomes. Different forms of proteasomes are known. The role of immunoproteasomes (iPs) and intermediate proteasomes (intPs) is emerging. Here, using a CRISPR-Cas9 nickase technology a panel of four cell lines was obtained. Cells of histiocytic lymphoma, colorectal adenocarcinoma, cervix adenocarcinoma and hepatocarcinoma origin were modified to express proteasomes with mCherry-tagged β5i subunit, which is a catalytic subunit of iPs and intPs. Importantly, the chimeric gene expression in modified cells is under control of endogenous regulatory mechanisms and was increased following IFN-γ and/or TNF-α stimulation. Fluorescent proteasomes are catalytically active and were distributed within the nucleus and cytoplasm of the modified cells. RNAseq revealed marginal differences in gene expression profile between modified and initial cell lines, predominate metabolic pathways and a pattern of expressed receptors were determined for each cell line. Using obtained cell-lines it was shown that anti-cancer drugs ruxolitinib, vincristine and gefetinib stimulate the expression of β5i-containing proteasomes which might have an impact on the disease prognosis. Taken together, obtained cell lines represent convenient platform to study the immunoproteasome gene expression, localization of iPs and intPs, association of proteasomes with other proteins and many other aspects of proteasome biology under the influence of various drugs and conditions in real time and in living cells.

2021-09-14 | GSE183592 | GEO

B1b cell homeostasis is maintained by CD40 in atherosclerosis

Project description:B1b cell homeostasis is maintained by CD40 in atherosclerosis

| PRJNA772716 | ENA

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

Data files for manuscript "Lactate homeostasis is maintained through regulation of glycolysis and lipolysis"

Project description:Data files for manuscript "Lactate homeostasis is maintained through regulation of glycolysis and lipolysis"

2024-11-01 | MSV000096276 | MassIVE

A cell-based platform for the investigation of immunoproteasome subunit β5i expression and biology of β5i-containing proteasomes

Project description:A cell-based platform for the investigation of immunoproteasome subunit β5i expression and biology of β5i-containing proteasomes

| PRJNA761383 | ENA

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