scholarly journals MptpB, a virulence factor from Mycobacterium tuberculosis, exhibits triple-specificity phosphatase activity

2007 ◽  
Vol 406 (1) ◽  
pp. 13-18 ◽  
Author(s):  
Nicola Beresford ◽  
Sumayya Patel ◽  
Jane Armstrong ◽  
Balázs Szöor ◽  
Anthony P. Fordham-Skelton ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Substrate Specificity ◽  
Phosphatase Activity ◽  
Virulence Factor ◽  
Protein Phosphatase ◽  
Host Cells ◽  
Lipid Phosphatases ◽  
Phosphoinositide Phosphatase ◽  
Dual Specificity Protein Phosphatase

Bacterial pathogens have developed sophisticated mechanisms of evading the immune system to survive in infected host cells. Central to the pathogenesis of Mycobacterium tuberculosis is the arrest of phagosome maturation, partly through interference with PtdIns signalling. The protein phosphatase MptpB is an essential secreted virulence factor in M. tuberculosis. A combination of bioinformatics analysis, enzyme kinetics and substrate-specificity characterization revealed that MptpB exhibits both dual-specificity protein phosphatase activity and, importantly, phosphoinositide phosphatase activity. Mutagenesis of conserved residues in the active site signature indicates a cysteine-based mechanism of dephosphorylation and identifies two new catalytic residues, Asp165, essential in catalysis, and Lys164, apparently involved in substrate specificity. Sequence similarities with mammalian lipid phosphatases and a preference for phosphoinositide substrates suggests a potential novel role of MptpB in PtdIns metabolism in the host and reveals new perspectives for the role of this phosphatase in mycobacteria pathogenicity.

Substrate Specificity of IphP, a Cyanobacterial Dual-Specificity Protein Phosphatase with MAP Kinase Phosphatase Activity†

Biochemistry ◽  
1996 ◽  
Vol 35 (23) ◽  
pp. 7566-7572 ◽  
Author(s):  
L. Daniel Howell ◽  
Charmaine Griffiths ◽  
Lynelle W. Slade ◽  
Malcolm Potts ◽  
Peter J. Kennelly
Keyword(s):  
Substrate Specificity ◽  
Map Kinase ◽  
Phosphatase Activity ◽  
Protein Phosphatase ◽  
Dual Specificity ◽  
Map Kinase Phosphatase ◽  
Dual Specificity Protein Phosphatase ◽  
Specificity Protein

scholarly journals SopB promotes phosphatidylinositol 3-phosphate formation on Salmonella vacuoles by recruiting Rab5 and Vps34

2008 ◽  
Vol 182 (4) ◽  
pp. 741-752 ◽  
Author(s):  
Gustavo V. Mallo ◽  
Marianela Espina ◽  
Adam C. Smith ◽  
Mauricio R. Terebiznik ◽  
Ainel Alemán ◽  
...  
Keyword(s):  
Phosphatase Activity ◽  
Virulence Factor ◽  
Pi3 Kinase ◽  
Bacterial Virulence ◽  
Host Cells ◽  
Salmonella Infection ◽  
Outer Leaflet ◽  
Phosphoinositide Phosphatase ◽  
Bacterial Virulence Factor ◽  
Phosphatidylinositol 3

Salmonella colonizes a vacuolar niche in host cells during infection. Maturation of the Salmonella-containing vacuole (SCV) involves the formation of phosphatidylinositol 3-phosphate (PI(3)P) on its outer leaflet. SopB, a bacterial virulence factor with phosphoinositide phosphatase activity, was proposed to generate PI(3)P by dephosphorylating PI(3,4)P2, PI(3,5)P2, and PI(3,4,5)P3. Here, we examine the mechanism of PI(3)P formation during Salmonella infection. SopB is required to form PI(3,4)P2/PI(3,4,5)P3 at invasion ruffles and PI(3)P on nascent SCVs. However, we uncouple these events experimentally and reveal that SopB does not dephosphorylate PI(3,4)P2/PI(3,4,5)P3 to produce PI(3)P. Instead, the phosphatase activity of SopB is required for Rab5 recruitment to the SCV. Vps34, a PI3-kinase that associates with active Rab5, is responsible for PI(3)P formation on SCVs. Therefore, SopB mediates PI(3)P production on the SCV indirectly through recruitment of Rab5 and its effector Vps34. These findings reveal a link between phosphoinositide phosphatase activity and the recruitment of Rab5 to phagosomes.

scholarly journals Mycobacterium tuberculosis adhesins: potential biomarkers as anti-tuberculosis therapeutic and diagnostic targets

Microbiology ◽  
2014 ◽  
Vol 160 (9) ◽  
pp. 1821-1831 ◽  
Author(s):  
Viveshree S. Govender ◽  
Saiyur Ramsugit ◽  
Manormoney Pillay
Keyword(s):  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
Control Strategies ◽  
Host Cells ◽  
Tuberculosis Control ◽  
Surface Molecules ◽  
Host Pathogen Interaction ◽  
Bacterial Aggregation ◽  
Insight Into

Adhesion to host cells is a precursor to host colonization and evasion of the host immune response. Conversely, it triggers the induction of the immune response, a process vital to the host’s defence against infection. Adhesins are microbial cell surface molecules or structures that mediate the attachment of the microbe to host cells and thus the host–pathogen interaction. They also play a crucial role in bacterial aggregation and biofilm formation. In this review, we discuss the role of adhesins in the pathogenesis of the aetiological agent of tuberculosis, Mycobacterium tuberculosis. We also provide insight into the structure and characteristics of some of the characterized and putative M. tuberculosis adhesins. Finally, we examine the potential of adhesins as targets for the development of tuberculosis control strategies.

scholarly journals Coxiella burnetii inhibits host immunity by a protein phosphatase adapted from glycolysis

2021 ◽  
Vol 119 (1) ◽  
pp. e2110877119
Author(s):  
Yong Zhang ◽  
Jiaqi Fu ◽  
Shuxin Liu ◽  
Lidong Wang ◽  
Jiazhang Qiu ◽  
...  
Keyword(s):  
Phosphatase Activity ◽  
Coxiella Burnetii ◽  
Protein Phosphatase ◽  
Bacterial Pathogen ◽  
Sugar Metabolism ◽  
Host Immunity ◽  
Host Cells ◽  
Functional Screening ◽  
Type Iv ◽  
Fructose 1,6 Bisphosphate

Coxiella burnetii is a bacterial pathogen that replicates within host cells by establishing a membrane-bound niche called the Coxiella-containing vacuole. Biogenesis of this compartment requires effectors of its Dot/Icm type IV secretion system. A large cohort of such effectors has been identified, but the function of most of them remain elusive. Here, by a cell-based functional screening, we identified the effector Cbu0513 (designated as CinF) as an inhibitor of NF-κB signaling. CinF is highly similar to a fructose-1,6-bisphosphate (FBP) aldolase/phosphatase present in diverse bacteria. Further study reveals that unlike its ortholog from Sulfolobus tokodaii, CinF does not exhibit FBP phosphatase activity. Instead, it functions as a protein phosphatase that specifically dephosphorylates and stabilizes IκBα. The IκBα phosphatase activity is essential for the role of CinF in C. burnetii virulence. Our results establish that C. burnetii utilizes a protein adapted from sugar metabolism to subvert host immunity.

scholarly journals The Dual-Specificity Protein Phosphatase Yvh1p Acts Upstream of the Protein Kinase Mck1p in Promoting Spore Development in Saccharomyces cerevisiae

1999 ◽  
Vol 181 (17) ◽  
pp. 5219-5224 ◽  
Author(s):  
Alexander E. Beeser ◽  
Terrance G. Cooper
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein Phosphatase ◽  
Vegetative Growth ◽  
Nitrogen Starvation ◽  
Developmental Pathway ◽  
Dual Specificity ◽  
Dual Specificity Protein Phosphatase ◽  
Specificity Protein ◽  
Spore Maturation

ABSTRACT Diploid Saccharomyces cerevisiae cells induce YVH1 expression and enter the developmental pathway, leading to sporulation when starved for nitrogen. We show that yvh1 disruption causes a defect in spore maturation; overexpression of MCK1or IME1 suppresses this yvh1 phenotype. Whilemck1 mutations are epistatic to those in yvh1relative to spore maturation, overexpression of MCK1 does not suppress the yvh1 slow-vegetative-growth phenotype. We conclude that (i) Yvh1p functions earlier than Mck1p and Ime1p in the signal transduction cascade that regulates sporulation and is triggered by nitrogen starvation and (ii) the role of Yvh1p in gametogenesis can be genetically distinguished from its role in vegetative growth.

scholarly journals The cGAS/STING Pathway Is Important for Dendritic Cell Activation but Is Not Essential to Induce Protective Immunity against Mycobacterium tuberculosis Infection

2018 ◽  
Vol 10 (3) ◽  
pp. 239-252 ◽  
Author(s):  
Fabio V. Marinho ◽  
Sulayman Benmerzoug ◽  
Stephanie  Rose ◽  
Priscila C. Campos ◽  
João T. Marques ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Cell Activation ◽  
Body Weight Gain ◽  
Host Cells ◽  
Health Concern ◽  
Wild Type ◽  
Activation Markers ◽  
Sting Pathway

Mycobacterium tuberculosis (Mtb) infection remains a major public health concern. The STING (stimulator of interferon genes) pathway contributes to the cytosolic surveillance of host cells. Most studies on the role of STING activation in Mtb infection have focused on macrophages. Moreover, a detailed investigation of the role of STING during Mtb infection in vivo is required. Here, we deciphered the involvement of STING in the activation of dendritic cells (DCs) and the host response to Mtb infection in vivo. In DCs, this adaptor molecule was important for Ifn-β expression and IL-12 production as well as for the surface expression of the activation markers CD40 and CD86. We also documented that Mtb DNA induces STING activation in murine fibroblasts. In vivo Mtb aerogenic infection induced the upregulation of the STING and cGAS (cyclic GMP-AMP synthase) genes, and Ifn-β pulmonary expression was dependent on both sensors. However, mice deficient for STING or cGAS presented a similar outcome to wild-type controls, with no major alterations in body weight gain, bacterial burden, or survival. Lung inflammation, proinflammatory cytokine production, and inflammatory cell recruitment were similar in STING- and cGAS-deficient mice compared to wild-type controls. In summary, although the STING pathway seems to be crucial for DC activation during Mtb infection, it is dispensable for host protection in vivo.

scholarly journals Immunohistochemical Expression of Dual-Specificity Protein Phosphatase 4 in Patients with Colorectal Adenocarcinoma

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Jongmin Sim ◽  
Kijong Yi ◽  
Hyunsung Kim ◽  
Hyein Ahn ◽  
Yumin Chung ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Colorectal Adenocarcinoma ◽  
Malignant Tumors ◽  
Male Gender ◽  
Rank Test ◽  
Log Rank Test ◽  
Dual Specificity ◽  
Dual Specificity Protein Phosphatase ◽  
Specificity Protein

The role of dual-specificity protein phosphatase 4 (DUSP4) appears to vary with the type of malignant tumors and is still controversial. The purpose of our study was to clarify the exact role of DUSP4 expression in colorectal adenocarcinoma. We constructed tissue microarrays and investigated DUSP4 expression by immunohistochemistry. DUSP4 was more frequently expressed in adenocarcinomas and lymph node/distant metastases compared to that in normal colorectal tissues and tubular adenomas (P<0.001). Mean DUSP4 expression score was significantly higher in malignant tumors than in benign lesions (P<0.001). DUSP4 expression was significantly correlated with older age (P=0.017), male gender (P=0.036), larger tumor size (P=0.014), nonmucinous tumor type (P=0.023), and higher T stage (P=0.040). Kaplan-Meier survival curves revealed a significant effect of DUSP4 expression on both overall survival and disease-free survival in AJCC stage I (P=0.008andP=0.003, resp., log-rank test) and male gender (P=0.017andP=0.049, resp., log-rank test). DUSP4 protein is frequently upregulated in colorectal adenocarcinoma and may play an important role in carcinogenesis and cancer progression and may be a marker of adverse prognosis.

scholarly journals CTL0511 from Chlamydia trachomatis Is a Type 2C Protein Phosphatase with Broad Substrate Specificity

2016 ◽  
Vol 198 (13) ◽  
pp. 1827-1836 ◽  
Author(s):  
Ja E. Claywell ◽  
Derek J. Fisher
Keyword(s):  
Chlamydia Trachomatis ◽  
Substrate Specificity ◽  
Protein Phosphorylation ◽  
Phosphatase Activity ◽  
Protein Phosphatase ◽  
Bacterial Pathogens ◽  
Dependent Manner ◽  
Content Type ◽  
Bacterial Physiology ◽  
Broad Substrate Specificity

ABSTRACTProtein phosphorylation has become increasingly recognized for its role in regulating bacterial physiology and virulence.Chlamydiaspp. encode two validated Hanks'-type Ser/Thr protein kinases, which typically function with cognate protein phosphatases and appear capable of global protein phosphorylation. Consequently, we sought to identify a Ser/Thr protein phosphatase partner for the chlamydial kinases. CTL0511 fromChlamydia trachomatisL2 434/Bu, which has homologs in all sequencedChlamydiaspp., is a predicted type 2C Ser/Thr protein phosphatase (PP2C). Recombinant maltose-binding protein (MBP)-tagged CTL0511 (rCTL0511) hydrolyzedp-nitrophenyl phosphate (pNPP), a generic phosphatase substrate, in a MnCl2-dependent manner at physiological pH. Assays using phosphopeptide substrates revealed that rCTL0511 can dephosphorylate phosphorylated serine (P-Ser), P-Thr, and P-Tyr residues using either MnCl2or MgCl2, indicating that metal usage can alter substrate preference. Phosphatase activity was unaffected by PP1, PP2A, and PP3 phosphatase inhibitors, while mutation of conserved PP2C residues significantly inhibited activity. Finally, phosphatase activity was detected in elementary body (EB) and reticulate body (RB) lysates, supporting a role for protein dephosphorylation in chlamydial development. These findings support that CTL0511 is a metal-dependent protein phosphatase with broad substrate specificity, substantiating a reversible phosphorylation network inC. trachomatis.IMPORTANCEChlamydiaspp. are obligate intracellular bacterial pathogens responsible for a variety of diseases in humans and economically important animal species. Our work demonstrates thatChlamydiaspp. produce a PP2C capable of dephosphorylating P-Thr, P-Ser, and P-Tyr and thatChlamydia trachomatisEBs and RBs possess phosphatase activity. In conjunction with the chlamydial Hanks'-type kinases Pkn1 and PknD, validation of CTL0511 fulfills the enzymatic requirements for a reversible phosphoprotein network. As protein phosphorylation regulates important cellular processes, including metabolism, differentiation, and virulence, in other bacterial pathogens, these results set the stage for elucidating the role of global protein phosphorylation in chlamydial physiology and virulence.

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