scholarly journals EfgA is a conserved formaldehyde sensor that halts bacterial translation in response to elevated formaldehyde

2020 ◽  
Author(s):  
Jannell V. Bazurto ◽  
Dipti D. Nayak ◽  
Tomislav Ticak ◽  
Milya Davlieva ◽  
Jessica A. Lee ◽  
...  
Keyword(s):  
Stress Response ◽  
Methylotrophic Bacteria ◽  
Translational Machinery ◽  
Cellular Processes ◽  
Translational Activity ◽  
Interaction Partners ◽  
Single Protein ◽  
Stress Response System ◽  
Sense And Respond ◽  
Enzymatic Detoxification

AbstractNormal cellular processes give rise to toxic metabolites that cells must mitigate. Formaldehyde is a universal stressor and potent metabolic toxin that is generated in organisms from bacteria to humans. Methylotrophic bacteria such as Methylorubrum extorquens face an acute challenge due to their production of formaldehyde as an obligate central intermediate of single-carbon metabolism. Mechanisms to sense and respond to formaldehyde were speculated to exist in methylotrophs for decades but had never been discovered. Here we identify a member of the DUF336 domain family, named efgA for enhanced formaldehyde growth, that plays an important role in endogenous formaldehyde stress response in M. extorquens PA1 and is found almost exclusively in methylotrophic taxa. Our experimental analyses reveal that EfgA is a formaldehyde sensor that inhibits translation in response to elevated levels of formaldehyde. Heterologous expression of EfgA in Escherichia coli increases formaldehyde resistance, indicating that its interaction partners are widespread and conserved and may include translational machinery. EfgA represents the first example of a formaldehyde stress response system that does not involve enzymatic detoxification. Thus, EfgA comprises a unique stress response mechanism in bacteria, whereby a single protein directly senses elevated levels of a toxic intracellular metabolite and modulates translational activity.

scholarly journals EfgA is a conserved formaldehyde sensor that leads to bacterial growth arrest in response to elevated formaldehyde

PLoS Biology ◽  
2021 ◽  
Vol 19 (5) ◽  
pp. e3001208
Author(s):  
Jannell V. Bazurto ◽  
Dipti D. Nayak ◽  
Tomislav Ticak ◽  
Milya Davlieva ◽  
Jessica A. Lee ◽  
...  
Keyword(s):  
Stress Response ◽  
Methylotrophic Bacteria ◽  
Cellular Processes ◽  
Toxic Metabolites ◽  
Interaction Partners ◽  
Single Protein ◽  
Stress Response System ◽  
Sense And Respond ◽  
Potential Damage ◽  
Enzymatic Detoxification

Normal cellular processes give rise to toxic metabolites that cells must mitigate. Formaldehyde is a universal stressor and potent metabolic toxin that is generated in organisms from bacteria to humans. Methylotrophic bacteria such as Methylorubrum extorquens face an acute challenge due to their production of formaldehyde as an obligate central intermediate of single-carbon metabolism. Mechanisms to sense and respond to formaldehyde were speculated to exist in methylotrophs for decades but had never been discovered. Here, we identify a member of the DUF336 domain family, named efgA for enhanced formaldehyde growth, that plays an important role in endogenous formaldehyde stress response in M. extorquens PA1 and is found almost exclusively in methylotrophic taxa. Our experimental analyses reveal that EfgA is a formaldehyde sensor that rapidly arrests growth in response to elevated levels of formaldehyde. Heterologous expression of EfgA in Escherichia coli increases formaldehyde resistance, indicating that its interaction partners are widespread and conserved. EfgA represents the first example of a formaldehyde stress response system that does not involve enzymatic detoxification. Thus, EfgA comprises a unique stress response mechanism in bacteria, whereby a single protein directly senses elevated levels of a toxic intracellular metabolite and safeguards cells from potential damage.

scholarly journals Systematic Humanization of the Yeast Cytoskeleton Discerns Functionally Replaceable from Divergent Human Genes

Genetics ◽  
2020 ◽  
Vol 215 (4) ◽  
pp. 1153-1169 ◽  
Author(s):  
Riddhiman K. Garge ◽  
Jon M. Laurent ◽  
Aashiq H. Kachroo ◽  
Edward M. Marcotte
Keyword(s):  
Gene Families ◽  
Growth Defect ◽  
Gene Duplications ◽  
Yeast Gene ◽  
Macromolecular Transport ◽  
Cellular Processes ◽  
Growth Defects ◽  
Yeast Strains ◽  
Human Genes ◽  
Interaction Partners

Many gene families have been expanded by gene duplications along the human lineage, relative to ancestral opisthokonts, but the extent to which the duplicated genes function similarly is understudied. Here, we focused on structural cytoskeletal genes involved in critical cellular processes, including chromosome segregation, macromolecular transport, and cell shape maintenance. To determine functional redundancy and divergence of duplicated human genes, we systematically humanized the yeast actin, myosin, tubulin, and septin genes, testing ∼81% of human cytoskeletal genes across seven gene families for their ability to complement a growth defect induced by inactivation or deletion of the corresponding yeast ortholog. In five of seven families—all but α-tubulin and light myosin, we found at least one human gene capable of complementing loss of the yeast gene. Despite rescuing growth defects, we observed differential abilities of human genes to rescue cell morphology, meiosis, and mating defects. By comparing phenotypes of humanized strains with deletion phenotypes of their interaction partners, we identify instances of human genes in the actin and septin families capable of carrying out essential functions, but failing to fully complement the cytoskeletal roles of their yeast orthologs, thus leading to abnormal cell morphologies. Overall, we show that duplicated human cytoskeletal genes appear to have diverged such that only a few human genes within each family are capable of replacing the essential roles of their yeast orthologs. The resulting yeast strains with humanized cytoskeletal components now provide surrogate platforms to characterize human genes in simplified eukaryotic contexts.

scholarly journals Functional Roles of Bromodomain Proteins in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3606
Author(s):  
Samuel P. Boyson ◽  
Cong Gao ◽  
Kathleen Quinn ◽  
Joseph Boyd ◽  
Hana Paculova ◽  
...  
Keyword(s):  
Open Chromatin ◽  
Structural Domains ◽  
Pharmacological Agents ◽  
Functional Roles ◽  
Cellular Processes ◽  
Protein Interactome ◽  
Interaction Partners ◽  
Recent Developments ◽  
Bromodomain Proteins ◽  
Chromatin Configuration

Histone acetylation is generally associated with an open chromatin configuration that facilitates many cellular processes including gene transcription, DNA repair, and DNA replication. Aberrant levels of histone lysine acetylation are associated with the development of cancer. Bromodomains represent a family of structurally well-characterized effector domains that recognize acetylated lysines in chromatin. As part of their fundamental reader activity, bromodomain-containing proteins play versatile roles in epigenetic regulation, and additional functional modules are often present in the same protein, or through the assembly of larger enzymatic complexes. Dysregulated gene expression, chromosomal translocations, and/or mutations in bromodomain-containing proteins have been correlated with poor patient outcomes in cancer. Thus, bromodomains have emerged as a highly tractable class of epigenetic targets due to their well-defined structural domains, and the increasing ease of designing or screening for molecules that modulate the reading process. Recent developments in pharmacological agents that target specific bromodomains has helped to understand the diverse mechanisms that bromodomains play with their interaction partners in a variety of chromatin processes, and provide the promise of applying bromodomain inhibitors into the clinical field of cancer treatment. In this review, we explore the expression and protein interactome profiles of bromodomain-containing proteins and discuss them in terms of functional groups. Furthermore, we highlight our current understanding of the roles of bromodomain-containing proteins in cancer, as well as emerging strategies to specifically target bromodomains, including combination therapies using bromodomain inhibitors alongside traditional therapeutic approaches designed to re-program tumorigenesis and metastasis.

scholarly journals Hanks-Type Serine/Threonine Protein Kinases and Phosphatases in Bacteria: Roles in Signaling and Adaptation to Various Environments

2018 ◽  
Vol 19 (10) ◽  
pp. 2872 ◽  
Author(s):  
Monika Janczarek ◽  
José-María Vinardell ◽  
Paulina Lipa ◽  
Magdalena Karaś
Keyword(s):  
Dna Binding ◽  
Essential Role ◽  
Current Knowledge ◽  
Response Regulator ◽  
Protein Targets ◽  
Regulatory Pathways ◽  
Translational Machinery ◽  
Signaling Systems ◽  
Cellular Processes ◽  
Division Cell

Reversible phosphorylation is a key mechanism that regulates many cellular processes in prokaryotes and eukaryotes. In prokaryotes, signal transduction includes two-component signaling systems, which involve a membrane sensor histidine kinase and a cognate DNA-binding response regulator. Several recent studies indicate that alternative regulatory pathways controlled by Hanks-type serine/threonine kinases (STKs) and serine/threonine phosphatases (STPs) also play an essential role in regulation of many different processes in bacteria, such as growth and cell division, cell wall biosynthesis, sporulation, biofilm formation, stress response, metabolic and developmental processes, as well as interactions (either pathogenic or symbiotic) with higher host organisms. Since these enzymes are not DNA-binding proteins, they exert the regulatory role via post-translational modifications of their protein targets. In this review, we summarize the current knowledge of STKs and STPs, and discuss how these enzymes mediate gene expression in prokaryotes. Many studies indicate that regulatory systems based on Hanks-type STKs and STPs play an essential role in the regulation of various cellular processes, by reversibly phosphorylating many protein targets, among them several regulatory proteins of other signaling cascades. These data show high complexity of bacterial regulatory network, in which the crosstalk between STK/STP signaling enzymes, components of TCSs, and the translational machinery occurs. In this regulation, the STK/STP systems have been proved to play important roles.

The oxidative stress response system

2004 ◽  
pp. 59-76 ◽  
Author(s):  
André Korsloot ◽  
Cornelis A.M. van Gestel ◽  
Nico M. van Straalen
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Oxidative Stress Response ◽  
Response System ◽  
Stress Response System

scholarly journals Ser/Thr phospho-regulation by PknB and Stp mediates bacterial quiescence and antibiotic persistence in Staphylococcus aureus

2021 ◽  
Author(s):  
Markus Huemer ◽  
Srikanth Mairpady Shambat ◽  
Sandro Pereira ◽  
Lies Van Gestel ◽  
Judith Bergada-Pijuan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Ribosomal Proteins ◽  
Environmental Changes ◽  
Acid Stress ◽  
Elongation Factor ◽  
Growth Delay ◽  
Lag Phase ◽  
Cellular Processes ◽  
Translational Activity

Staphylococcus aureus colonizes 30 to 50% of healthy adults and can cause a variety of diseases, ranging from superficial to life-threatening invasive infections such as bacteraemia and endocarditis. Often, these infections are chronic and difficult-to-treat despite adequate antibiotic therapy. Most antibiotics act on metabolically active bacteria in order to eradicate them. Thus, bacteria with minimized energy consumption resulting in metabolic quiescence, have increased tolerance to antibiotics. The most energy intensive process in cells - protein synthesis - is attenuated in bacteria entering into quiescence. Eukaryote-like serine/threonine kinases (STKs) and phosphatases (STPs) can fine-tune essential cellular processes, thereby enabling bacteria to quickly respond to environmental changes and to modulate quiescence. Here, we show that deletion of the only annotated functional STP, named Stp, in S. aureus leads to increased bacterial lag-phase and phenotypic heterogeneity under different stress challenges, including acidic pH, intracellular milieu and in vivo abscess environment. This growth delay was associated with reduced intracellular ATP levels and increased antibiotic persistence. Using phosphopeptide enrichment and mass spectrometry-based proteomics, we identified possible targets of Ser/Thr phosphorylation that regulate cellular processes and bacterial growth, such as ribosomal proteins including the essential translation elongation factor EF-G. Finally, we show that acid stress leads to a reduced translational activity in the stp deletion mutant indicating metabolic quiescence correlating with increased antibiotic persistence.

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