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Clostridium difficile
Published in Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward, Case Studies in Infectious Disease, 2010
Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward
Low levels of biotin also increase toxin production. During exponential growth, TcdC is high and it is believed to be an anti-sigma factor negatively regulating toxin production. TcdC mutants have been described. These strains produce increased amounts of toxins A and B in vitro, particularly in stationary phase. These mutant strains appear to be particularly virulent. TcdD is not an exotoxin per se, but a positive regulator of transcription of toxin genes and is also responsible for the temperature-dependent regulation of toxin production. The sigma factor TcdR is also a positive regulator, although it is itself under some form of regulation. Additionally, C. difficile has a luxS-type quorum-sensing signaling system, although evidence suggests that addition of the inducer (AI-2) has no effect on toxin production.
Regulation of flagellar motility and biosynthesis in enterohemorrhagic Escherichia coli O157:H7
Published in Gut Microbes, 2022
Hongmin Sun, Min Wang, Yutao Liu, Pan Wu, Ting Yao, Wen Yang, Qian Yang, Jun Yan, Bin Yang
In E. coli, including EHEC O157:H7, the expression of flagellar genes is a tightly regulated and highly energetic three-tier process (Figure 3).12 The Class I gene flhDC encodes proteins FlhD and FlhC, that assemble into the heterohexamer (FlhD4C2).14 The FlhD4C2 proteins complex binds to the DNA upstream of Class II genes, recruits RNA polymerase, and promotes σ70-dependent transcription (Figure 3).17 FliA is an alternate sigma factor (σ28), encoded by a Class II gene, specifically required for transcription initiation of Class III genes.18 FlgM acts as an anti-sigma factor that binds to FliA directly, preventing interaction with RNA polymerase and repressing FliA-dependent transcription until after hook-basal body are formed.19 Upon assembly of the basal body and secretion apparatus, FlgM is exported out of the cell, freeing FliA and allowing initiation of FliA-dependent transcription from Class III promoters.20 This three-tiered flagellar regulatory cascade helps bacteria, including EHEC O157:H7, to conserve biosynthetic resources and ensure the efficiency of flagellar assembly.
Cystic Fibrosis: Proteostatic correctors of CFTR trafficking and alternative therapeutic targets.
Published in Expert Opinion on Therapeutic Targets, 2019
John W. Hanrahan, Yukiko Sato, Graeme W. Carlile, Gregor Jansen, Jason C. Young, David Y. Thomas
Another potential therapeutic target attracting attention is SLC26A9, a Cl− channel and member of the solute carrier 26 transporter family that contributes to basal Cl− conductance in airway epithelia. SLC26A9 null mice develop mucus obstruction when challenged with proinflammatory cytokines, indicating it is required for efficient mucus clearance in inflamed airways [136]. A genome-wide association study (GWAS) identified SLC26A9 as a modifier of CF disease severity [137] and it was later shown to influence airway symptoms in a GWAS study of patients bearing the G551D mutation [138]. SLC26A9 physically interacts with CFTR and can increase the channel activity of CFTR in some cell types [139]. The transmembrane domains, regulatory (R) domain of CFTR and Sulphate Transporter Anti Sigma factor antagonist (STAS) domain, and mutual binding to PDZ domain proteins may all mediate the interaction between these two proteins although the functional significance of the interaction remains uncertain. SLC26A9 membrane localization and ion transport are both reduced significantly in cells expressing F508del-CFTR, likely due to retention in the Golgi due to increased interaction with CFTR Associated Ligand (CAL) [140] and/or increased ER retention and ERAD. Disrupting the interaction of SLC26A9 with F508del-CFTR should increase its trafficking and conductance at the cell surface and the restoration of SLC26A9 trafficking and potentiation of its channel activity are promising therapeutic strategies [138,141].
CFTR dysfunction in cystic fibrosis and chronic obstructive pulmonary disease
Published in Expert Review of Respiratory Medicine, 2018
Elena Fernandez Fernandez, Chiara De Santi, Virginia De Rose, Catherine M. Greene
Based on the sequence of the CFTR protein, a structure was proposed that showed similarity to proteins in the ATP-binding cassette (ABC) transporter family [3]. The CFTR protein is embedded in the apical membrane of epithelial cells and is made up of distinct structural domains, including two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain (R) The R region is unique to CFTR, as are the long N- and C-terminal extensions, which are 80 and 30 residues in length, respectively. The R domain is phosphorylated by the protein kinases A (PKA), C (PKC), and 2 (CK2) and is dependent on the presence of intracellular ATP [5]. CFTR activity is likely regulated by a large number of other proteins including post-synaptic density 95/disk-large/zona occludens 1 (PDZ) interacting proteins and sulfate transporter and anti-sigma factor antagonist (STAS) domain interactors [6]. The NBDs contain conserved motifs for ATP binding and hydrolysis.