Abstract
Plague caused by Yersinia pestis is one of the deadliest diseases. However, many molecular mechanisms of bacterial virulence remain unclear. This study engaged in the discovery of small open reading frame (sORF)-encoded peptides (SEPs) in Y. pestis. An integrated proteogenomic pipeline was established, and an atlas containing 76 SEPs was described. Bioinformatic analysis indicated that 20% of these SEPs were secreted or localized to the transmembrane and that 33% contained functional domains. Two SEPs, named SEPs-yp1 and -yp2 and encoded in noncoding regions, were selected by comparative peptidomics analysis under host-specific environments and high-salinity stress. They displayed important roles in the regulation of antiphagocytic capability in a thorough functional assay. Remarkable attenuation of virulence in mice was observed in the SEP-deleted mutants. Further global proteomic analysis indicated that SEPs-yp1 and -yp2 affected the bacterial metabolic pathways, and SEP-yp1 was associated with the bacterial virulence by modulating the expression of key virulence factors of the Yersinia type III secretion system. Our study provides a rich resource for research on Y. pestis and plague, and the findings on SEP-yp1 and SEP-yp2 shed light on the molecular mechanism of bacterial virulence.
Highlights
Plague caused by Yersinia pestis is one of the deadliest diseases
Three modules were integrated into this pipeline, including parallel SEP prediction from RNA-sequencing (RNA-seq) data, discovery by refined peptidomics approaches, and curation based on homolog search and spectrum inspection, resulting in an atlas of 76 Y. pestis SEPs
An integrated proteogenomic pipeline enables the discovery of SEPs in Y. pestis
Summary
Plague caused by Yersinia pestis is one of the deadliest diseases. many molecular mechanisms of bacterial virulence remain unclear. Emerging evidence indicates that small open-reading frame (sORF)-encoded peptides (SEPs) play important roles in the biological processes of bacteria[5,6,7,8], which either act as signaling factors by binding to receptors or assist other regulatory proteins or complexes in exerting functions[9] These SEPs were reported to be involved in various biological processes of bacteria, including stress sensing (Prli42), spore formation (SpoVM and CmpA), cell division (MciZ, SidA and Blr), transport of ions and macromolecules (KdpF, AcrZ and SgrT), kinases and signal transduction (MgrB and Sda), and act as membrane-bound enzymes (CydX, PmrR and MgtR) and chaperones (MntS, FbpB and FbpC)[5,6]. The description of the SEP atlas opens new avenues for research on Y. pestis and plague, and characterization of the two virulence-regulatory SEPs provides insights into the underlying mechanism of the bacterial pathogenicity
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