Rapid modulation of gene expression is a key feature for the success of bacteria, particularly for those that rapidly have to adapt to different niches. The lifecycles of Photorhabdus and Xenorhabdus involve a mutualistic association with nematodes as well as an entomopathogenic phase, both of which rely on the production of numerous specialized metabolites (SMs). Several regulators have been previously implicated in the regulation of SM production in these genera. However, the molecular mechanisms underlying the regulatory control of SM production, and especially the role of small regulatory RNAs, are unknown. Here we show that the Hfq-dependent small RNA, ArcZ, is required for SM production. We discovered that ArcZ directly base-pairs with the mRNA encoding HexA, a known repressor of SM production. We further demonstrate that the ArcZ regulon is not restricted to SM production, but rather modulates up to ~15% of the transcriptional output in both Photorhabdus and Xenorhabdus. Together, our study shows that small RNAs are key for SM production in these species, provides new targets for biosynthetic pathway manipulations, and offers a new tool for the (over-)production, isolation and identification of unknown natural products.
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