scholarly journals Ribosome protein mutant cells rely on the GR64 cluster of gustatory receptors for survival and proteostasis in Drosophila

2021 ◽  
Author(s):  
Michael Baumgartner Baumgartner ◽  
Iwo Kucinski ◽  
Eugenia Piddini
Keyword(s):  
Epithelial Cells ◽  
Ribosome Biogenesis ◽  
Gustatory Receptor ◽  
Taste Sensation ◽  
Gustatory Receptors ◽  
Proteotoxic Stress ◽  
Pathway Activation ◽  
Sugar Receptors ◽  
Mutant Cells ◽  
Stress Pathway

Mutations in ribosome protein (Rp) genes and ribosome biogenesis factors result in debilitating diseases, known as ribosomopathies. Recent studies in Drosophila have shown that cells heterozygous mutant for Rp genes (Rp/+) exhibit proteotoxic stress and aggregates, which drive stress pathway activation and apoptosis. Understanding how Rp/+ cells fend off proteotoxic stress could suggest mechanisms to ameliorate these and other conditions caused by proteotoxic stress. Here we find that Rp/+ epithelial cells express all six Gustatory Receptor 64 (Gr64) genes, a cluster of sugar receptors involved in taste sensation. We show that Rp/+ cells depend on Gr64 for survival and that loss of Gr64 autonomously exacerbates stress pathway activation and proteotoxic stress by negatively effecting autophagy and proteasome function in Rp/+ cells. This work identifies a non-canonical role in proteostasis maintenance for a family of gustatory receptors known for their function in neuronal sensation.

scholarly journals A ribosome assembly stress response regulates transcription to maintain proteome homeostasis

2019 ◽  
Author(s):  
Benjamin Albert ◽  
Isabelle C. Kos-Braun ◽  
Anthony Henras ◽  
Christophe Dez ◽  
Maria Paula Rueda ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stress Response ◽  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Target Genes ◽  
Insoluble Fraction ◽  
Ribosome Assembly ◽  
Proteotoxic Stress ◽  
Rapid Activation ◽  
Stress Pathway

AbstractRibosome biogenesis is a complex and energy-demanding process requiring tight coordination of ribosomal RNA (rRNA) and ribosomal protein (RP) production. Alteration of any step in this process may impact growth by leading to proteotoxic stress. Although the transcription factor Hsf1 has emerged as a central regulator of proteostasis, how its activity is coordinated with ribosome biogenesis is unknown. Here we show that arrest of ribosome biogenesis in the budding yeast S. cerevisiae triggers rapid activation of a highly specific stress pathway that coordinately up-regulates Hsf1 target genes and down-regulates RP genes. Activation of Hsf1 target genes requires neo-synthesis of RPs, which accumulate in an insoluble fraction, leading to sequestration of the RP transcriptional activator Ifh1. Our data suggest that levels of newly-synthetized RPs, imported into the nucleus but not yet assembled into ribosomes, work to continuously balance Hsf1 and Ifh1 activity, thus guarding against proteotoxic stress during ribosome assembly.

scholarly journals LKB1/p53/TIGAR/autophagy-dependent VEGF expression contributes to PM2.5-induced pulmonary inflammatory responses

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Huan Xu ◽  
Xiuduan Xu ◽  
Hongli Wang ◽  
Aodeng Qimuge ◽  
Shasha Liu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Bronchial Epithelial Cells ◽  
Vegf Expression ◽  
Bronchial Epithelial ◽  
Autophagy Induction ◽  
Pathway Activation ◽  
Pm2.5 Exposure

Abstract One of the health hazards of PM2.5 exposure is to induce pulmonary inflammatory responses. In our previous study, we demonstrated that exposing both the immortalized and primary human bronchial epithelial cells to PM2.5 results in a significant upregulation of VEGF production, a typical signaling event to trigger chronic airway inflammation. Further investigations showed that PM2.5 exposure strongly induces ATR/CHK1/p53 cascade activation, leading to the induction of DRAM1-dependent autophagy to mediate VEGF expression by activating Src/STAT3 pathway. In the current study, we further revealed that TIGAR was another transcriptional target of p53 to trigger autophagy and VEGF upregulation in Beas-2B cells after PM2.5 exposure. Furthermore, LKB1, but not ATR and CHK1, played a critical role in mediating p53/TIGAR/autophagy/VEGF pathway activation also by linking to Src/STAT3 signaling cascade. Therefore, on combination of the previous report, we have identified both ATR/CHK1/p53/DRAM1- and LKB1/p53/TIGAR- dependent autophagy in mediating VEGF production in the bronchial epithelial cells under PM2.5 exposure. Moreover, the in vivo study further confirmed VEGF induction in the airway potentially contributed to the inflammatory responses in the pulmonary vascular endothelium of PM2.5-treated rats. Therefore, blocking VEGF expression or autophagy induction might be the valuable strategies to alleviating PM2.5-induced respiratory injuries.

scholarly journals Ubiquitin proteomics reveals critical targets of the Nse1 RING domain in rDNA and genome stability

2021 ◽  
Author(s):  
Eva Ibars ◽  
Gemma Belli ◽  
Celia Casas ◽  
Joan Codina-Fabra ◽  
Marc Tarres ◽  
...  
Keyword(s):  
Ribosome Biogenesis ◽  
Genome Stability ◽  
Ring Domain ◽  
Transcriptional Elongation ◽  
Label Free ◽  
Dna Damage Tolerance ◽  
Cellular Processes ◽  
Ubiquitin E3 Ligase ◽  
Polymerase I ◽  
Mutant Cells

Ubiquitination controls numerous cellular processes, and its deregulation is associated to many pathologies. The Nse1 subunit in the Smc5/6 complex contains a RING domain with ubiquitin E3 ligase activity and important functions in genome integrity. However, Nse1-dependent ubiquitin targets remain largely unknown. Here, we use label-free quantitative proteomics to analyse the nuclear ubiquitinome of nse1-C274A RING mutant cells. Our results show that Nse1 impacts on the ubiquitination of several proteins involved in DNA damage tolerance, ribosome biogenesis and metabolism that, importantly, extend beyond canonical functions of the Smc5/6 complex in chromosome segregation. In addition, our analysis uncovers an unexpected connection between Nse1 and RNA polymerase I (RNAP I) ubiquitination. Specifically, Nse1 promotes the ubiquitination of K408 and K410 in A190, the largest subunit of RNAP I, to induce its degradation. We propose that this mechanism contributes to Smc5/6-dependent rDNA disjunction in response to transcriptional elongation defects.

scholarly journals dksA Is Required for Intercellular Spread of Shigella flexneri via an RpoS-Independent Mechanism

2001 ◽  
Vol 69 (9) ◽  
pp. 5742-5751 ◽  
Author(s):  
Scott A. Mogull ◽  
Laura J. Runyen-Janecky ◽  
Mei Hong ◽  
Shelley M. Payne
Keyword(s):  
Epithelial Cells ◽  
Cultured Cells ◽  
Shigella Flexneri ◽  
Cell Cytoplasm ◽  
Independent Mechanism ◽  
Virulence Protein ◽  
Intercellular Spread ◽  
Mutant Cells ◽  
And Oxidative Stress ◽  
Intracellular Analysis

ABSTRACT Pathogenesis of Shigella flexneri is dependent on the ability of the bacterium to invade and spread within epithelial cells. In this study, we identified dksA as a gene necessary for intercellular spread in, but not invasion of, cultured cells. The S. flexneri dksA mutant exhibited sensitivity to acid and oxidative stress, in part due to an effect of DksA on production of RpoS. However, an S. flexneri rpoS mutant formed plaques on tissue culture monolayers, thus excluding DksA regulation of RpoS as the mechanism responsible for the inability of the dksA mutant to spread intercellularly. Intracellular analysis of the dksA mutant indicates that it survived and divided within the Henle cell cytoplasm, but thedksA mutant cells were elongated, and some exhibited filamentation in the intracellular environment. Some of the S. flexneri dksA mutant cells showed aberrant localization of virulence protein IcsA, which may inhibit spread between epithelial cells.

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