Universal stress protein

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Universal Stress Protein A
USP A domain.png
UspA protein structure from Lactobacillus plantarum [1]
Identifiers
Symbollp_3663
Pfam PF00582
Pfam clan HUP
InterPro IPR006016
SCOP2 1mjh / SCOPe / SUPFAM

The universal stress protein (USP) domain is a superfamily of conserved genes which can be found in bacteria, archaea, fungi, protozoa and plants. [2] Proteins containing the domain are induced by many environmental stressors such as nutrient starvation, drought, extreme temperatures, high salinity, and the presence of uncouplers, antibiotics and metals. [2]

Contents

In the presence of these stressors, Usp genes are upregulated resulting in large quantities of Usp proteins being produced by the cell. The over production of USP genes allows the organisms to better cope with stresses by largely unknown mechanisms. However, the USPs will alter the expression of a variety of genes that help to cope with stress. [3]

Function

The protein structure of a Universal Stress Protein found in Haemophylus influenzae Haemophylus influenzae USP.png
The protein structure of a Universal Stress Protein found in Haemophylus influenzae

The primary function of this superfamily is to protect the organism from environmental stress such as exposure to UV light, which may induce genes containing the USP domain in order to protect the DNA and more generally the cell from further damage. [2] During bacterialstarvation the USP genes upregulated will often arrest cell growth and promote its metabolism to adapt to sparse nutrients. [2]

Recent research also suggests proteins containing this domain have functions beyond the realms of dealing with environmental stresses. [5] Nachin et al. demonstrated in Escherichia coli that USPs are involved in actions such as adhesion and motility. The researchers, through means of "knocking out" USP genes known as UspE and UspC, saw results suggesting an inability to swim and completely lack of motility, respectively. Conversely, mutants for genes UspF and UspG were shown to have enhanced swimming abilities. Therefore, mobility is affected both positively and negatively USPs within E. coli. This demonstrates USPs influence throughout the cell could be widespread for a number of reasons.

Additionally, in Halmonas elongate, there is a USP called TeaD has been described as a key regulator in the transport of Ectoine across the cell membrane. [6] This demonstrates how versatile USPs can be. Their function, while primarily encompasses increasing survival during stressful conditions, is not always limited to this.

Evolution

The ubiquitous nature of these proteins suggests the domain evolved in an ancestral species as well as highlighting the clear biological significance these proteins have in order to still be present in the three domains of life. It has been suggested that the USP A domain was part of an ancient protein family. This is due to the similarity in structure between many distantly related organisms. [7] Aravind et al. confirmed these ideas with extensive evolutionary analysis. Aravind suggested that these proteins were part of a much larger protein structural family which was present and diversified in our last universal common ancestor for all extant life. [7] The original function has been suggested to be a nucleotide binding domain which was implicated in signal transduction [8]

Structure

As the USP domain is widespread across many organisms, there is great diversity in the structures of these proteins. For Haemophilus influenzae, its UspA resides in the cytoplasm. The protein forms an asymmetric dimer with characteristic alpha and beta fold structures. There are differences among different bacteria in areas such as ATP binding sites. [2] In this case, UspA does not have ATP binding activity. Generally, USPs form dimers and have domains for nucleotide binding activity. However, as it is such a diverse group, often with little known about the exact structure, it’s not possible to comment on each USP. In addition to this, UspA may reside in different areas of the cell. For example, in this case it was in the cytoplasm but for others, it may be in the cell membrane. [9]

Bacteria

Much of the research into USP is done on bacteria, specifically E. coli (Strain K-12). Consequently, much is known about the USP domains in bacteria. In E. coli there are six families of USP domains which are present in more than 1000 different proteins. [10] The six families are Usp A, -C, -D, -E, -F and –G which are triggered by differing environmental insults and often act via varying mechanisms. [10]

UspA is the most commonly studied USP due to its widespread presence within bacterial genomes. UspA is especially implicated in the resistance of a huge number of stressors most notably tetracycline exposure and high temperatures, with the exception of not forming a response to cold shock. It is thought UspA is especially important to the recovery of E. coli following starvation of nutrients. [2] UspA during normal growth conditions does not seem to influence gene expression. However, during stressful conditions such as carbon starvation, UspA has been shown to have a global influence on gene expression. A proposed mechanism for such a change in gene expression is that UspA has been suggested to bind to DNA. When UspA is mutated, E. coli becomes far more vulnerable UV induced DNA damage. [11] It’s important to note the USP responses are independent of many other stress responses seen in bacteria such as rpoS. [12]

This schematic shows a generalised bacterial response to an environmental stress. In this case, it depicts increased levels of Nitric Oxide which stimulates Usp gene transcription. This results in an anti-stress response from the cell which may or may not include the responses listed within the diagram. Bacteria USP response.png
This schematic shows a generalised bacterial response to an environmental stress. In this case, it depicts increased levels of Nitric Oxide which stimulates Usp gene transcription. This results in an anti-stress response from the cell which may or may not include the responses listed within the diagram.

The induction of USP proteins have also been implicated in transitions not only in metabolism or growth but in changes in the colonies' entire phenotype. Bacterial colonies can produce formations known as biofilms. Zhang and colleagues demonstrated that USPs may be involved in the promotion of intertidal biofilms. [13] They observed that during stressful conditions involving metal ions and oxidative stresses that the biofilm phenotype would form. Upon analysis of these biofilms, it could be seen that there was a greatly upregulated level of UspA which Zhang suggests, may be involved with induction of biofilm formation. It is thought UspA may be involved in signalling processes which will upregulate genes involved with biofilm production. [12] With findings such as these, it's beginning to be accepted that USPs are acting using an extremely wide range of mechanisms to ensure cell survival.

Regulation

In bacteria, the USP genes can be regulated by sigma factors within RNA polymerases. This includes sigma factor σ70 which through binding to a single promoter region, upregulates the transcription of UspA in bacteria. The genes are regulated in a monocistronic fashion. [14] Additionally, UspA, UspC, UspD and UspE are over induced during stationary phase through regulation of RecA. RecA is known for its involvement in the repair of DNA via homologous recombination following damage. Consequently, the four Usp domain genes are thought to be mediating the management or protection of DNA. [15] Whatever the mechanism exhibited by the proteins, one thing which can be concluded is that USP domains are crucial for survival of many bacterial species. Gomes et al. found that UspA deletions in Listeria severely impaired survival as well as listeria’s stress response by in vitro and in vivo. [16]

USP domain genes are regulated by a number of proteins involved with growth, DNA repair and cell division. Notable positive regulation occurs via the action of ppGpp, RecA and FtsZ dependent regulatory pathways. USP domain genes are also under the negative control of FadR. [17]

Plants

Plants contain many hundreds of USP domains and genes. These genes are notably induced by environmental stresses such as drought. When a lack of hydration occurs, biochemical changes induced by the actions of USPs ensue. In response to drought, there is a reduction in photosynthetic carbon production as well as a reduction in energy metabolism. [18] These actions are suggested to occur due to their implications in increasing energy conservation. Water limiting conditions are a common environmental pressure which plants will need to cope with on a regular basis, depending on their habitat. These resistant phenotypes will have an increased survival as they allow the plant to conserve energy in times of restricted water which is key to glucose production through photosynthesis. [18]

Clinical significance

Tuberculosis

Mycobacterium tuberculosis, the infectious agent responsible for tuberculosis (TB), persists within an estimated two billion people. TB is known for its ability to transition into a latent state whereby there is slow growth but high persistence within the mammalian host in structures known as granulomas. [19] These granuloma structures are made up of various cellular materials and immune cells. These include macrophages, neutrophils, cellulose and fats. It has long been proposed that USPs play a significant role in the persistence of TB within the human host. This is due to observations of elevated Usp genes within M. tuberculosis in the latent granuloma stage of the infection. [20]

There are eight types of USPs within M. tuberculosis, all of which have an ATP binding domain. It has been found that within M. tuberculosis, these USPs are regulated by FtsK and FadR. [21] One recent finding shows that the induction of USPs within M. tuberculosis results in USP binding activity with intracellular cAMP which has indirect implications on transcription within the bacteria. [22]

Some of M. tuberculosis' USPs are suggested to be induced by the hypoxic conditions found within the granuloma. Specifically, Rv2623, a type of USP in M. tuberculosis, is induced by the presence of nitric oxide, reactive oxygen species and a downshift in pH. All of these conditions are suggested to be produced by the actions of macrophages which are particularly prevalent within the granuloma structures that are characteristic of TB latent infections. [20] These conditions have been found to upregulate a particular USP gene called rv2623, as well as an additional 50 genes involved in long-term persistence in the mammalian host. It was suggested this USP gene was involved in inducing the latent response within the mammalian host. This stage of the infection is currently chronic with no effective treatments. This makes these kinds of findings extremely valuable.

Rv2623 has an ATP binding domain which if knocked out results in a hyper-virulent form of the bacteria. [21] Understanding these processes aids researchers in their quest to provide effective treatment for those suffering from TB. Rv2623 is also a key biomarker aiding the diagnostic process for TB. Therefore, these USP genes could be crucial for the long-term survival of the bacteria, meaning that there may be potential therapeutic avenues of research to explore in treating latent TB. [23] This comes at a time whereby TB kills many thousands of people a day and is becoming increasing problematic to treat with the rise of multi-drug-resistant TB.

Salmonella

Similarly, USPs are crucial for the survival of Salmonella, the causative agent in Salmonellosis. In developing countries, food poisoning of this kind is a potentially life-threatening condition. The USPs have influence in growth arrest, stress responses and virulence. [24] UspA is induced by metabolic, oxidative and temperature related stress. In these conditions UspA is over produced through the transcriptional regulation by ppGpp and RecA. These responses have been suggested to be involved in the protection of DNA. As a result, UspA aids Salmonella to resist stressors produced by the mammalian immune system assisting in survival and hence, pathogenicity. [24] When UspA is inactivated in Salmonella, the mutants die prematurely, demonstrating how crucial these proteins are to survival and persistence. Again, understanding these processes may aid researchers in developing effective drugs to treat these infections. [24]

Related Research Articles

Biofilm Aggregation of bacteria or cells on a surface

A biofilm comprises any syntrophic consortium of microorganisms in which cells stick to each other and often also to a surface. These adherent cells become embedded within a slimy extracellular matrix that is composed of extracellular polymeric substances (EPSs). The cells within the biofilm produce the EPS components, which are typically a polymeric conglomeration of extracellular polysaccharides, proteins, lipids and DNA. Because they have three-dimensional structure and represent a community lifestyle for microorganisms, they have been metaphorically described as "cities for microbes".

Lac repressor

The lac repressor is a DNA-binding protein that inhibits the expression of genes coding for proteins involved in the metabolism of lactose in bacteria. These genes are repressed when lactose is not available to the cell, ensuring that the bacterium only invests energy in the production of machinery necessary for uptake and utilization of lactose when lactose is present. When lactose becomes available, it is firstly converted into allolactose by β-Galactosidase (lacZ) in bacteria. The DNA binding ability of lac repressor bound with allolactose is inhibited due to allosteric regulation, thereby genes coding for proteins involved in lactose uptake and utilization can be expressed.

Hsp70 Heat shock protein

The 70 kilodalton heat shock proteins are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an important part of the cell's machinery for protein folding, performing chaperoning functions, and helping to protect cells from the adverse effects of physiological stresses. Additionally, membrane-bound Hsp70s have been identified as a potential target for cancer therapies and their extracellularly localized counterparts have been identified as having both membrane-bound and membrane-free structures.

Nucleoid Region within a prokaryotic cell containing genetic material

The nucleoid is an irregularly shaped region within the prokaryotic cell that contains all or most of the genetic material. The chromosome of a prokaryote is circular, and its length is very large compared to the cell dimensions, so it needs to be compacted in order to fit. In contrast to the nucleus of a eukaryotic cell, it is not surrounded by a nuclear membrane. Instead, the nucleoid forms by condensation and functional arrangement with the help of chromosomal architectural proteins and RNA molecules as well as DNA supercoiling. The length of a genome widely varies and a cell may contain multiple copies of it.

GroEL

GroEL is a protein which belongs to the chaperonin family of molecular chaperones, and is found in many bacteria. It is required for the proper folding of many proteins. To function properly, GroEL requires the lid-like cochaperonin protein complex GroES. In eukaryotes the organellar proteins Hsp60 and Hsp10 are structurally and functionally nearly identical to GroEL and GroES, respectively, due to their endosymbiotic origin.

Filamentation

Filamentation, also termed conditional filamentation, is the anomalous growth of certain bacteria, such as Escherichia coli, in which cells continue to elongate but do not divide. The cells that result from elongation without division have multiple chromosomal copies. In the absence of antibiotics or other stressors, filamentation occurs at a low frequency in bacterial populations. The increased cell length can protecting bacteria from protozoan predation and neutrophil phagocytosis by making ingestion of cells more difficult. Filamentation is also thought to protect bacteria from antibiotics, and is associated with other aspects of bacterial virulence such as biofilm formation. The number and length of filaments within a bacterial population increases when the bacteria are treated with various chemical and physical agents. Some of the key genes involved in filamentation in E. coli include sulA and minCD.

The gene rpoS encodes the sigma factor sigma-38, a 37.8 kD protein in Escherichia coli. Sigma factors are proteins that regulate transcription in bacteria. Sigma factors can be activated in response to different environmental conditions. rpoS is transcribed in late exponential phase, and RpoS is the primary regulator of stationary phase genes. RpoS is a central regulator of the general stress response and operates in both a retroactive and a proactive manner: it not only allows the cell to survive environmental challenges, but it also prepares the cell for subsequent stresses (cross-protection). The transcriptional regulator CsgD is central to biofilm formation, controlling the expression of the curli structural and export proteins, and the diguanylate cyclase, adrA, which indirectly activates cellulose production. The rpoS gene most likely originated in the gammaproteobacteria.

fis

fis is an E. coli gene encoding the Fis protein. The regulation of this gene is more complex than most other genes in the E. coli genome, as Fis is an important protein which regulates expression of other genes. It is supposed that fis is regulated by H-NS, IHF and CRP. It also regulates its own expression (autoregulation). Fis is one of the most abundant DNA binding proteins in Escherichia coli under nutrient-rich growth conditions.

Malate synthase

In enzymology, a malate synthase (EC 2.3.3.9) is an enzyme that catalyzes the chemical reaction

Binding immunoglobulin protein Protein-coding gene in the species Homo sapiens

Binding immunoglobulin protein (BiP) also known as (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) or (Byun1) is a protein that in humans is encoded by the HSPA5 gene.

DNA damage-inducible transcript 3 Protein-coding gene in the species Homo sapiens

DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-apoptotic transcription factor that is encoded by the DDIT3 gene. It is a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding transcription factors. The protein functions as a dominant-negative inhibitor by forming heterodimers with other C/EBP members, preventing their DNA binding activity. The protein is implicated in adipogenesis and erythropoiesis and has an important role in the cell's stress response.

Bacterial small RNAs (sRNA) are small RNAs produced by bacteria; they are 50- to 500-nucleotide non-coding RNA molecules, highly structured and containing several stem-loops. Numerous sRNAs have been identified using both computational analysis and laboratory-based techniques such as Northern blotting, microarrays and RNA-Seq in a number of bacterial species including Escherichia coli, the model pathogen Salmonella, the nitrogen-fixing alphaproteobacterium Sinorhizobium meliloti, marine cyanobacteria, Francisella tularensis, Streptococcus pyogenes, the pathogen Staphylococcus aureus, and the plant pathogen Xanthomonas oryzae pathovar oryzae. Bacterial sRNAs affect how genes are expressed within bacterial cells via interaction with mRNA or protein, and thus can affect a variety of bacterial functions like metabolism, virulence, environmental stress response, and structure.

Bacterial DNA binding protein

In molecular biology, bacterial DNA binding proteins are a family of small, usually basic proteins of about 90 residues that bind DNA and are known as histone-like proteins. Since bacterial binding proteins have a diversity of functions, it has been difficult to develop a common function for all of them. They are commonly referred to as histone-like and have many similar traits with the eukaryotic histone proteins. Eukaryotic histones package DNA to help it to fit in the nucleus, and they are known to be the most conserved proteins in nature. Examples include the HU protein in Escherichia coli, a dimer of closely related alpha and beta chains and in other bacteria can be a dimer of identical chains. HU-type proteins have been found in a variety of bacteria and archaea, and are also encoded in the chloroplast genome of some algae. The integration host factor (IHF), a dimer of closely related chains which is suggested to function in genetic recombination as well as in translational and transcriptional control is found in Enterobacteria and viral proteins including the African swine fever virus protein A104R.

BolA-like protein family

In molecular biology, the BolA-like protein family consists of the morpho-protein BolA from Escherichia coli, the Fra2 protein from Saccharomyces cerevisiae, and various homologs. The BolA protein is a DNA-binding regulator; the Fra2 protein is an iron sulfur cluster protein that binds Grx3/4 and is involved in regulating iron levels .

Bacterial morphological plasticity refers to changes in the shape and size that bacterial cells undergo when they encounter stressful environments. Although bacteria have evolved complex molecular strategies to maintain their shape, many are able to alter their shape as a survival strategy in response to protist predators, antibiotics, the immune response, and other threats.

Oxidation response is stimulated by a disturbance in the balance between the production of reactive oxygen species and antioxidant responses, known as oxidative stress. Active species of oxygen naturally occur in aerobic cells and have both intracellular and extracellular sources. These species, if not controlled, damage all components of the cell, including proteins, lipids and DNA. Hence cells need to maintain a strong defense against the damage. The following table gives an idea of the antioxidant defense system in bacterial system.

Single-stranded binding protein

Single-stranded binding proteins (SSBs) are a class of proteins that have been identified in both viruses and organisms from bacteria to humans.

Curli A proteinaceous extracellular fiber produced by enteric bacteria

The Curli protein is a type of amyloid fiber produced by certain strains of enterobacteria. They are extracellular fibers located on bacteria such as E. coli and Salmonella spp. These fibers serve to promote cell community behavior through biofilm formation in the extracellular matrix. Amyloids are associated with several human neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, and prion diseases. The study of curli may help to understand human diseases thought to arise from improper amyloid fiber formation. The curli pili are generally assembled through the extracellular nucleation/precipitation pathway.

GrpE

GrpE is a bacterial nucleotide exchange factor that is important for regulation of protein folding machinery, as well as the heat shock response. It is a heat-inducible protein and during stress it prevents unfolded proteins from accumulating in the cytoplasm. Accumulation of unfolded proteins in the cytoplasm can lead to cell death.

Pho regulon

The Phosphate (Pho) regulon is a regulatory mechanism used for the conservation and management of inorganic phosphate within the cell. It was first discovered in Escherichia coli as an operating system for the bacterial strain, and was later identified in other species. The Pho system is composed of various components including extracellular enzymes and transporters that are capable of phosphate assimilation in addition to extracting inorganic phosphate from organic sources. This is an essential process since phosphate plays an important role in cellular membranes, genetic expression, and metabolism within the cell. Under low nutrient availability, the Pho regulon helps the cell survive and thrive despite a depletion of phosphate within the environment. When this occurs, phosphate starvation-inducible (psi) genes activate other proteins that aid in the transport of inorganic phosphate.

References

  1. ↑ Tan K, et al. (2008). "The crystal structure of an universal stress protein UspA family protein from Lactobacillus plantarum WCFS1". Protein Data Bank. doi:10.2210/pdb3fg9/pdb..
  2. 1 2 3 4 5 6 Siegele DA, et al. (2005). "Universal Stress Proteins in Escherichia coli". Journal of Bacteriology . 187 (18): 6253–6254. doi:10.1128/jb.187.18.6253-6254.2005. PMC   1236659 . PMID   16159755..
  3. ↑ Tkaczuk KL, et al. (2013). "Structural and functional insight into the universal stress protein family". Evolutionary Applications . 6 (3): 434–449. doi:10.1111/eva.12057. PMC   3673472 . PMID   23745136..
  4. ↑ Sousa MC (2001). "Structure of Haemophylus influenzae Universal Stress Protein At 1.85A Resolution". Structure . 9: 1135–1141. doi:10.2210/pdb1jmv/pdb..
  5. ↑ Nachin L, et al. (2005). "Differential Roles of the Universal Stress Proteins of Escherichia coli in Oxidative Stress Resistance, Adhesion, and Motility". Journal of Bacteriology . 187 (18): 6265–6272. doi:10.1128/JB.187.18.6265-6272.2005. PMC   1236625 . PMID   16159758..
  6. ↑ Schweikhard ES, et al. (2010). "Structure and function of the universal stress protein TeaD and its role in regulating the ectoine transporter TeaABC of Halomonas elongata DSM 2581(T)". Biochemistry . 49 (10): 2194–2204. doi:10.1021/bi9017522. PMID   20113006..
  7. 1 2 Aravind L, et al. (2002). "Monophyly of class I aminoacyl tRNA synthetase, USPA, ETFP, photolyase, and PP-ATPase nucleotide-binding domains: implications for protein evolution in the RNA". Protein . 48 (1): 1–14. doi:10.1002/prot.10064. PMID   12012333. S2CID   32908067..
  8. ↑ Becker JD (2001). "The nodulin vfENOD18 is an ATP-binding protein in infected cells of Vicia faba L. nodules". Plant Mol Biol . 47 (6): 749–759. doi:10.1023/A:1013664311052. PMID   11785936. S2CID   24974722..
  9. ↑ Sousa MC (2001). "Structure of the universal stress protein of Haemophilus influenzae". Bichemical Sciences . 9 (12): 1135–1141. doi: 10.1016/s0969-2126(01)00680-3 . PMID   11738040.
  10. 1 2 Bateman A (2004). "The Pfam protein families database". Nucleic Acids Research . 32 (90001): 138–141. doi:10.1093/nar/gkh121. PMC   308855 . PMID   14681378.
  11. ↑ O'Toole R (2003). "Universal stress proteins and Mycobacterium tuberculosis". Research in Microbiology . 154 (6): 387–392. doi:10.1016/S0923-2508(03)00081-0. PMID   12892844.
  12. 1 2 Gustavsson N (2002). "The universal stress protein paralogues of Escherichia coli are co-ordinately regulated and co-operate in the defence against DNA damage". Molecular Microbiology . 43 (1): 107–117. doi: 10.1046/j.1365-2958.2002.02720.x . PMID   11849540. S2CID   25979289.
  13. 1 2 Zhang W (2013). "Adaptation of intertidal biofilm communities is driven by metal ion and oxidative stresses". Scientific Reports . 3: 3180. Bibcode:2013NatSR...3E3180Z. doi:10.1038/srep03180. PMC   3822395 . PMID   24212283.
  14. ↑ Kvint K (2013). "The bacterial universal stress protein: function and regulation". Curr Opin Microbiol . 6 (2): 140–145. doi:10.1016/S1369-5274(03)00025-0. PMID   12732303.
  15. ↑ Diez A (2002). "The universal stress protein A of Escherichia coli is required for resistance to DNA damaging agents and is regulated by a RecA/FtsK-dependent regulatory pathway". Molecular Microbiology . 36 (6): 1494–1503. doi: 10.1046/j.1365-2958.2000.01979.x . PMID   10931298. S2CID   22239740.
  16. ↑ Gomes CS (2011). "Universal Stress Proteins Are Important for Oxidative and Acid Stress Resistance and Growth of Listeria monocytogenes EGD-e In Vitro and In Vivo". PLOS ONE. 6 (9): e24965. Bibcode:2011PLoSO...624965S. doi: 10.1371/journal.pone.0024965 . PMC   3184099 . PMID   21980369.
  17. ↑ "The Universal Stress Protein A". www.uniprot.org. Uniprot. 2015-03-25. Retrieved 2015-03-25.
  18. 1 2 Isokpehi RD (2011). "Identification of drought-responsive universal stress proteins in viridiplantae". bioinform Biol Insights . 5: 41–58. doi:10.4137/BBI.S6061. PMC   3045048 . PMID   21423406.
  19. ↑ Ramakrishnan L (2012). "Revisiting the role of the granuloma in tuberculosis". Nature Reviews . 12 (5): 352–366. doi:10.1038/nri3211. PMID   22517424. S2CID   1139969.
  20. 1 2 O'Toole R (2003). "Universal stress proteins and Mycobacterium tuberculosis". Research in Microbiology . 154 (6): 387–392. doi:10.1016/S0923-2508(03)00081-0. PMID   12892844.
  21. 1 2 Drumm JE (2009). "Mycobacterium tuberculosis universal stress protein Rv2623 regulates bacillary growth by ATP-Binding: requirement for establishing chronic persistent infection". PLoS Pathog. 5 (5): e1000460. doi:10.1371/journal.ppat.1000460. PMC   2682197 . PMID   19478878.
  22. ↑ Banerjee A (2015). "A Universal Stress Protein (USP) in Mycobacteria binds cAMP". The Journal of Biological Chemistry . 12 (20): 1–28. doi: 10.1074/jbc.M115.644856 . PMC   4432290 . PMID   25802331.
  23. ↑ Hingley-Wilson SM (2010). "Individual Mycobacterium tuberculosis universal stress protein homologues are dispensable in vitro". Tuberculosis . 90 (4): 236–244. doi:10.1016/j.tube.2010.03.013. PMC   2914252 . PMID   20541977.
  24. 1 2 3 Liu WT (2007). "Role of the universal stress protein UspA of Salmonella in growth arrest, stress and virulence". Microbial Pathogenesis . 42 (1): 2–10. doi:10.1016/j.micpath.2006.09.002. PMID   17081727.
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