Shehryar Ahmad, Boyuan Wang, Matthew D Walker, Hiu-Ki R Tran, Peter J Stogios, Alexei Savchenko, Robert A Grant, Andrew G McArthur, Michael T Laub, John C Whitney
Bacteria have evolved sophisticated mechanisms to inhibit the growth of competitors1 . One such mechanism involves type VI secretion systems, which bacteria can use to inject antibacterial toxins directly into neighbouring cells. Many of these toxins target the integrity of the cell envelope, but the full range of growth inhibitory mechanisms remains unknown2 . Here we identify a type VI secretion effector, Tas1, in the opportunistic pathogen Pseudomonas aeruginosa. The crystal structure of Tas1 shows that it is similar to enzymes that synthesize (p)ppGpp, a broadly conserved signalling molecule in bacteria that modulates cell growth rate, particularly in response to nutritional stress3 ...
November 6, 2019: Nature
He Song, Madushini N Dharmasena, Chao Wang, Gary X Shaw, Scott Cherry, Joseph E Tropea, Ding J Jin, Xinhua Ji
Rapid adaptation to environmental changes is crucial for bacterial survival. Almost all bacteria possess a conserved stringent response system to prompt transcriptional and metabolic responses toward stress. The adaptive process relies on alarmones, guanosine pentaphosphate (pppGpp) and tetraphosphate (ppGpp), to regulate global gene expression. The ppGpp is more potent than pppGpp in the regulatory activity and pppGpp phosphohydrolase (GppA) plays a key role in (p)ppGpp homeostasis. Sharing a similar domain structure, GppA is indistinguishable from exopolyphosphatase (PPX), which mediates the metabolism of cellular inorganic polyphosphate...
November 2, 2019: FEBS Journal
Anushya Petchiappan, Sujay Y Naik, Dipankar Chatterji
Stringent response is a conserved stress response mechanism in which bacteria employ the second messengers guanosine tetraphosphate and guanosine pentaphosphate (collectively termed '(p)ppGpp') to reprogram their cellular processes under stress. In mycobacteria, these alarmones govern a multitude of cellular phenotypes such as cell division, biofilm formation, antibiotic tolerance and long-term survival. Mycobacterium smegmatis possesses the bifunctional RelMsm as a (p)ppGpp synthetase and hydrolase. In addition, it contains a short alarmone synthetase (SAS) MS_RHII-RSD (renamed RelZ) which contains a RNaseH domain in tandem with the (p)ppGpp synthetase domain...
October 28, 2019: Journal of Bacteriology
Eaazhisai Kandiah, Diego Carriel, Pierre Simon Garcia, Jan Felix, Manuel Banzhaf, George Kritikos, Maria Bacia-Verloop, Céline Brochier-Armanet, Sylvie Elsen, Irina Gutsche
The only enzyme responsible for cadaverine production in the major multidrug-resistant human pathogen Pseudomonas aeruginosa is the lysine decarboxylase LdcA. This enzyme modulates the general polyamine homeostasis, promotes growth, and reduces bacterial persistence during carbenicillin treatment. Here we present a 3.7-Å resolution cryoelectron microscopy structure of LdcA. We introduce an original approach correlating phylogenetic signal with structural information and reveal possible recombination among LdcA and arginine decarboxylase subfamilies within structural domain boundaries...
October 21, 2019: Structure
Daniel J Bennison, Sophie E Irving, Rebecca M Corrigan
Many facets of ribosome biogenesis and function, including ribosomal RNA (rRNA) transcription, 70S assembly and protein translation, are negatively impacted upon induction of a nutrient stress-sensing signalling pathway termed the stringent response. This stress response is mediated by the alarmones guanosine tetra- and penta-phosphate ((p)ppGpp), the accumulation of which leads to a massive cellular response that slows growth and aids survival. The 70S bacterial ribosome is an intricate structure, with assembly both complex and highly modular...
October 24, 2019: Cells
Zhuo Ma, Kayla King, Maha Alqahtani, Madeline Worden, Parthasarathy Muthuraman, Christopher L Cioffi, Chandra Shekhar Bakshi, Meenakshi Malik
Francisella tularensis is a Gram-negative bacterium responsible for causing tularemia in the northern hemisphere. F. tularensis has long been developed as a biological weapon due to its ability to cause severe illness upon inhalation of as few as ten organisms and, based on its potential to be used as a bioterror agent is now classified as a Tier 1 Category A select agent by the CDC. The stringent response facilitates bacterial survival under nutritionally challenging starvation conditions. The hallmark of stringent response is the accumulation of the effector molecules ppGpp and (p)ppGpp known as stress alarmones...
2019: PloS One
Yanan Zhang, Doron Teper, Jin Xu, Nian Wang
The bacterial stringent response is a response to nutrition deprivation and other stress conditions. In Gram-negative bacteria, this process is mediated by the small signal molecules guanosine pentaphosphate pppGpp and guanosine tetraphosphate ppGpp (collectively referred to as (p)ppGpp), and the RNA polymerase-binding transcription factor DksA. The (p)ppGpp synthetase RelA and the bifunctional (p)ppGpp synthase/hydrolase SpoT are responsible for cellular (p)ppGpp levels. Here, we investigated the roles of DksA and (p)ppGpp in the virulence traits of Xanthomonas citri subsp...
November 2019: Molecular Plant Pathology
Galina V Smirnova, Aleksey V Tyulenev, Kseniya V Bezmaternykh, Nadezda G Muzyka, Vadim Y Ushakov, Oleg N Oktyabrsky
Increased intracellular cysteine poses a potential danger to cells due to the high ability of cysteine to reduce free iron and promote the Fenton reaction. Here, we studied ways to maintain cysteine homeostasis in E. coli cells while inhibiting protein synthesis with valine or chloramphenicol. When growing wild-type bacteria on minimal medium with sulfate, an excess of cysteine resulting from the inhibition of protein synthesis is mainly incorporated into glutathione (up to 90%), which, therefore, can be considered as cysteine buffer...
October 15, 2019: Amino Acids
Ning Yang, Shujie Xie, Nga-Yeung Tang, Mei Yee Choi, Ying Wang, Rory M Watt
During the stringent response, bacteria synthesize guanosine-3',5'-bis(diphosphate) (ppGpp) and guanosine-5'-triphosphate 3'-diphosphate (pppGpp), which act as secondary messengers to promote cellular survival and adaptation. (p)ppGpp 'alarmones' are synthesized and/or hydrolyzed by proteins belonging to the RelA/SpoT Homologue (RSH) family. Many bacteria also encode 'small alarmone synthetase' (SAS) proteins (e.g. RelP, RelQ) which may also be capable of synthesizing a third alarmone: guanosine-5'-phosphate 3'-diphosphate (pGpp)...
2019: PloS One
Marie Delaby, Gaël Panis, Patrick H Viollier
Many bacteria acquire dissemination and virulence traits in G1-phase. CtrA, an essential and conserved cell cycle transcriptional regulator identified in the dimorphic alpha-proteobacterium Caulobacter crescentus, first activates promoters in late S-phase and then mysteriously switches to different target promoters in G1-phase. We uncovered a highly conserved determinant in the DNA-binding domain (DBD) of CtrA uncoupling this promoter switch. We also show that it reprograms CtrA occupancy in stationary cells inducing a (p)ppGpp alarmone signal perceived by the RNA polymerase beta subunit...
October 10, 2019: Nucleic Acids Research
Brent W Anderson, Kuanqing Liu, Christine Wolak, Katarzyna Dubiel, Fukang She, Kenneth A Satyshur, James L Keck, Jue D Wang
The alarmone (p)ppGpp regulates diverse targets, yet its target specificity and evolution remain poorly understood. Here we elucidate the mechanism by which basal (p)ppGpp inhibits the purine salvage enzyme HPRT by sharing a conserved motif with its substrate PRPP. Intriguingly, HPRT regulation by (p)ppGpp varies across organisms and correlates with HPRT oligomeric forms. (p)ppGpp-sensitive HPRT exists as a PRPP-bound dimer or an apo- and (p)ppGpp-bound tetramer, where a dimer-dimer interface triggers allosteric structural rearrangements to enhance (p)ppGpp inhibition...
September 25, 2019: ELife
Dariusz Nowicki, Monika Maciąg-Dorszyńska, Krystyna Bogucka, Agnieszka Szalewska-Pałasz, Anna Herman-Antosiewicz
Isothiocyanates (ITCs) derived from cruciferous plants reveal antibacterial activity, although detailed mechanism is not fully elucidated. Recently it has been reported that ITCs induce the stringent response in Escherichia coli strains. The aim of this work was to determine whether two isothiocyanates, sulforaphane (SFN) and phenethyl isothiocyanate (PEITC), similarly as in E. coli induce stringent response in Bacillus subtilis, model Gram(+) bacterium, and test their potency against a panel of clinical isolates belonging to Gram(+) or Gram(-) groups...
September 23, 2019: Scientific Reports
Andreas Latoscha, Mirka E Wörmann, Natalia Tschowri
Antibiotic producing Streptomyces sense and respond to environmental signals by using nucleotide second messengers, including (p)ppGpp, cAMP, c-di-GMP and c-di-AMP. As summarized in this review, these molecules are important message carriers that coordinate the complex Streptomyces morphological transition from filamentous growth to sporulation along with the secondary metabolite production. Here, we provide an overview of the enzymes that make and break these second messengers and suggest candidates for (p)ppGpp and cAMP enzymes to be studied...
September 19, 2019: Microbiology
René Lysdal Bærentsen, Ditlev Egeskov Brodersen, Yong Everett Zhang
In our recent publication (Zhang et al. , 2019), we demonstrate an interesting mode of regulation of purine metabolism unique to Proteobacteria. In this microreview, we would like to reflect on the ideas put forward, with special focus on protein domain architecture of the enzyme involved, its orthologues in plants, and the implications of the differential effects observed between binding of the two alarmone molecules, ppGpp (guanosine 3',5'-bisdiphosphate) and pppGpp (guanosine-5'-triphosphate-3'-diphosphate)...
July 16, 2019: Microbial Cell
Kathryn Jane Turnbull, Ievgen Dzhygyr, Søren Lindemose, Vasili Hauryliuk, Mohammad Roghanian
Amino acid starvation in Escherichia coli activates the enzymatic activity of the stringent factor RelA, leading to accumulation of the alarmone nucleotide (p)ppGpp. The alarmone acts as an intercellular messenger to regulate transcription, translation and metabolism to mediate bacterial stress adaptation. The enzymatic activity of RelA is subject to multi-layered allosteric control executed both by ligands - such as "starved" ribosomal complexes, deacylated tRNA and pppGpp - and by individual RelA domains...
2019: Frontiers in Microbiology
Natalie Verstraeten, Sotirios Gkekas, Cyrielle Ines Kint, Babette Deckers, Bram Van den Bergh, Pauline Herpels, Elen Louwagie, Wouter Knapen, Dorien Wilmaerts, Liselot Dewachter, Maarten Fauvart, Ranjan Kumar Singh, Jan Michiels, Wim Versées
Obg is a versatile GTPase that plays a pivotal role in bacterial persistence. We previously showed that the Escherichia coli homolog ObgE exerts this activity through transcriptional activation of a toxin-antitoxin module and subsequent membrane depolarization. Here we assessed the role of G-domain functionality in ObgE-mediated persistence. Through screening of a mutant library, we identified five obgE alleles (with substitutions G166V, D246G, S270I, N283I, and I313N) that have lost their persistence function and no longer activate hokB expression...
September 9, 2019: Molecular Microbiology
Alison Wood, Sophie E Irving, Daniel J Bennison, Rebecca M Corrigan
Ribosome assembly cofactors are widely conserved across all domains of life. One such group, the ribosome-associated GTPases (RA-GTPase), act as molecular switches to coordinate ribosome assembly. We previously identified the Staphylococcus aureus RA-GTPase Era as a target for the stringent response alarmone (p)ppGpp, with binding leading to inhibition of GTPase activity. Era is highly conserved throughout the bacterial kingdom and is essential in many species, although the function of Era in ribosome assembly is unclear...
August 29, 2019: PLoS Genetics
Xiaohui Gao, Jinki Yeom, Eduardo A Groisman
All cells use proteases to maintain protein homeostasis. The proteolytic systems known as the N-degron pathways recognize signals at the N terminus of proteins and bring about the degradation of these proteins. The ClpS protein enforces the N-degron pathway in bacteria and bacteria-derived organelles by targeting proteins harboring leucine, phenylalanine, tryptophan, or tyrosine at the N terminus for degradation by the protease ClpAP. We now report that ClpS binds, and ClpSAP degrades, proteins still harboring the N-terminal methionine...
August 26, 2019: Proceedings of the National Academy of Sciences of the United States of America
Varsha Jha, Nishant A Dafale, Hemant J Purohit
The phosphorus availability in soil ranged from <0.01 to 1 ppm and found limiting for the utilization by plants. Hence, phosphate solubilizing bacteria (PSB) proficiently fulfill the phosphorus requirement of plants in an eco-friendly manner. The PSB encounter dynamic and challenging environmental conditions viz., high temperature, osmotic, acid, and climatic changes often hamper their activity and proficiency. The modern trend is shifting from isolation of the PSB to their genetic potentials and genome annotation not only for their better performance in the field trials but also to study their ability to cope up with stresses...
October 2019: Microbiological Research
Yingpeng Xie, Xiaolong Shao, Xin Deng
Pseudomonas syringae is a model phytopathogenic bacterium that uses the type III secretion system (T3SS) to cause lethal diseases in staple crops and thus presents a threat to food security worldwide. Great progress has been made in delineating the biochemical mechanisms and cellular targets of T3SS effectors, but less is known about the signalling pathways and molecular mechanisms of T3SS regulators. In recent years, thanks to the popularity and power of genome-wide mutant screening and high-throughput sequencing, new regulatory proteins (such as RhpR, AefR, AlgU and CvsR) and proteases (such as Lon and RhpP) have been identified as T3SS regulators in P...
August 13, 2019: Environmental Microbiology
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