A noncanonical transcriptional regulation in natural product biosynthesis

TenA (transcription enhancement) family proteins are widespread in bacteria, yet their functions in regulating natural product biosynthesis remain largely unexplored. Here, we report that LysR2, a TenA-family protein encoded by the lysolipin I biosynthetic gene cluster, acts as a transcriptional activator. Genetic and biochemical analyses reveal that LysR2 employs a noncanonical mechanism. Lacking a standard DNA-binding domain, it does not bind target promoters directly. Instead, LysR2 activates transcription by specifically binding to the pathway-specific repressor, LysR1. This protein–protein interaction displaces LysR1 from its cognate promoter, thereby derepressing the transcription of the biosynthetic gene cluster. Our work provides the first experimental evidence for a regulatory role of a TenA-family protein and elucidates a unique indirect activation mechanism that broadens the paradigm of transcriptional regulation in bacterial natural product biosynthesis.