An intramembrane sensory circuit monitors sortase A-mediated processing of streptococcal adhesins

Jeffrey W. Hall, Bruno P. Lima, Gaetan G. Herbomel, Tata Gopinath, Le Anna McDonald, Michael T. Shyne, John K. Lee, Jens Kreth, Karen F. Ross, Gianluigi Veglia, Mark C. Herzberg

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Bacterial adhesins mediate adhesion to substrates and biofilm formation. Adhesins of the LPXTG family are posttranslationally processed by the cell membrane-localized peptidase sortase A, which cleaves the LPXTG motif. This generates a short C-terminal peptide (C-pep) that remains in the cell membrane, whereas the mature adhesin is incorporated into the cell wall. Genes encoding adhesins of the oral bacterium Streptococcus gordonii were differentially expressed depending on whether the bacteria were isolated from saliva or dental plaque and appeared to be coordinately regulated. Deletion of sspA and sspB (sspAB), both of which encode LPXTG-containing adhesins, unexpectedly enhanced adhesion and biofilm formation. C-peps produced from a model LPXTG-containing adhesin localized to the cell membrane and bound to and inhibited the intramembrane sensor histidine kinase SGO_1180, thus preventing activation of the cognate response regulator SGO_1181. The absence of SspAB C-peps induced the expression of the scaCBA operon encoding the lipoprotein adhesin ScaA, which was sufficient to preserve and even enhance biofilm formation. This C-pep-driven regulatory circuit also exists in pathogenic streptococci and is likely conserved among Gram-positive bacteria. This quality control mechanism ensures that the bacteria can form biofilms under diverse environmental conditions and may play a role in optimizing adhesion and biofilm formation.

Original languageEnglish (US)
Article numbereaas9941
JournalScience signaling
Issue number580
StatePublished - May 7 2019

Bibliographical note

Funding Information:
We thank A. P. Caldwell for studies on the cotranscription of pavB-1180-1181. Appreciation is extended to H. Jenkinson, University of Bristol, for providing wild-type S. gordonii DL1 and J. Merritt, Oregon Health Sciences University, for helpful discussions about construction of the pJHMD1 mutagenesis cassette. We thank B. D. Guenther for identification of potential S. gordonii HKs and J. Abrahante of the University of Minnesota Genomics Center for expert assistance with next-generation transcriptomics analyses. We extend appreciation to G. Dunny of the Department of Microbiology and Immunology at the University of Minnesota for advice about the conduct of this study and the writing of this manuscript. We also thank the former and current members of the Herzberg and Svenstater labs (Malmö University) for their critical reading and feedback on this manuscript. Funding: This work was supported by National Institute of Dental and Craniofacial Research grants 1R01DE02561801A1 (to M.C.H.), T90DE0227232 and F32DE02578 (to J.W.H.), 1K08DE027705-01A1 (to B.P.L.), and GM 64742 (to G.V.); the University of Minnesota Summer Dental Student Research Fellowship Program (to Alita Caldwell); and the NIDCR-NIH intramural program (to G.G.H.). The NMR experiments were carried out at the Minnesota NMR Center. The transcriptomics analysis was completed at the University of Minnesota Genomics Center. Support to M.C.H. is also acknowledged from the University of Minnesota Office of the Vice President for Research and the School of Dentistry. Author contributions: J.W.H. constructed virtually all of the mutants reported, designed and executed experiments, analyzed data, and drafted the manuscript. G.G.H. performed SIM studies. B.P.L. performed in vivo studies of adhesin expression on S. gordonii. J.K.L. designed and executed the purification scheme for SspA C-pep and SGO_1180 and incorporation into lipid vesicles. T.G. and L.M. executed NMR studies. M.T.S. supervised and reviewed the statistical analysis. J.K. performed the early studies showing that C-pep complements loss of corresponding adhesins and edited the manuscript. K.F.R. designed experiments, analyzed data, and edited the manuscript. G.V. designed and supervised NMR experiments, analyzed data, and contributed to the writing of the manuscript. M.C.H. developed the hypothesis, analyzed data, contributed to the writing and editing of the manuscript, and directed the project. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.

Publisher Copyright:
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