Silencing cryptic specialized metabolism in Streptomyces by the nucleoid-associated protein Lsr2

Abstract

Lsr2 is a nucleoid-associated protein conserved throughout the actinobacteria, including the antibiotic-producing Streptomyces. Streptomyces species encode paralogous Lsr2 proteins (Lsr2 and Lsr2-like, or LsrL), and we show here that of the two, Lsr2 has greater functional significance. We found that Lsr2 binds AT-rich sequences throughout the chromosome, and broadly represses gene expression. Strikingly, specialized metabolic clusters were over-represented amongst its targets, and the cryptic nature of many of these clusters appears to stem from Lsr2-mediated repression. Manipulating Lsr2 activity in model species and uncharacterized isolates resulted in the production of new metabolites not seen in wild type strains. Our results suggest that the transcriptional silencing of biosynthetic clusters by Lsr2 may protect Streptomyces from the inappropriate expression of specialized metabolites, and provide global control over Streptomyces’ arsenal of signaling and antagonistic compounds.

Nucleoid Associated Proteins: The Small Organizers That Help to Cope With Stress

“…Most NAPs show rather low sequence specificity for binding; however, their binding sites are often AT-rich, which is a characteristic feature of gene promoters (Kahramanoglou et al, 2011;Prieto et al, 2012;Odermatt et al, 2018). All bacterial species possess NAPs, some of which are unique for a given genus and/or species (Datta et al, 2019;Gehrke et al, 2019;Liu et al, 2019). The NAPs of E. coli are the best studied examples (Wold et al, 1996;Ali Azam et al, 1999;Ryan et al, 2002;Dillon and Dorman, 2010;Verma et al, 2019).…”

Deciphering the Rules Underlying Xenogeneic Silencing and Counter-Silencing of Lsr2-like Proteins Using CgpS of Corynebacterium glutamicum as a Model

“…The nucleoid-associated protein Lsr2 is conserved throughout the phylum of Actinobacteria, where it plays an important role in the xenogeneic silencing of horizontally acquired genomic regions (4,18,19,39). The Lsr2-like protein CgpS was recently described as a classical XS protein silencing the expression of cryptic prophage elements and further horizontally acquired elements in C. glutamicum (4).…”

“…In contrast to mycobacteria and corynebacterial species, Streptomyces species typically encode two Lsr2-like proteins. Here, the prototypical lsr2 gene, showing the highest sequence identity to mycobacterial Lsr2, was recently described to silence the expression of specialized metabolic clusters (39). Considering the important role of Lsr2 proteins in the medically and biotechnologically important phylum of Actinobacteria, a detailed mechanistic understanding of Lsr2 binding in vivo is relevant as a potential drug target and for the identification novel bioactive compounds.…”

Deciphering the rules underlying xenogeneic silencing and counter-silencing of Lsr2-like proteins

“…In contrast to mycobacteria and corynebacterial species, Streptomyces typically encode two Lsr2-like proteins. Here, the prototypical lsr2 gene, showing the highest sequence identity to mycobacterial Lsr2, was recently described to silence the expression of specialized metabolic clusters (39). Considering the important role of Lsr2 proteins in the medically and biotechnologically important phylum of actinobacteria, a detailed mechanistic understanding of Lsr2 binding in vivo is relevant as a potential drug target and for the identification novel bioactive compounds.…”