Girolline is a sequence-context specific modulator of eIF5A activity
Natural products have a long history of providing potent probes into protein biosynthesis, with  numerous molecules serving as valuable therapeutics. The marine natural product girolline has  been described as an inhibitor of protein synthesis. Here, we demonstrate that it is not a general  translation inhibitor but represents a sequence-specific modulator of translation factor eIF5A.  Girolline interferes with ribosome-eIF5A interaction and induces ribosome stalling, primarily on  AAA-encoded lysine. Our data furthermore indicate that eIF5A plays a physiological role in  ribosome-associated quality control (RQC) and is important in maintaining the efficiency of  translational progress. Girolline, therefore, provides a potent tool compound for understanding  the interplay between protein production and quality control in a physiological setting and offers  a new and selective means of modulating gene expression. Overall design: Ribosome profiling and RNA-Seq of human cells treated with girolline