RNA Homeostasis Governed by Cell Type-Specific and Branched Feedback Loops Acting on NMD

SummaryNonsense-mediated mRNA decay (NMD) is a conserved RNA decay pathway that degrades aberrant mRNAs and directly regulates many normal mRNAs. This dual role for NMD raises the possibility that its magnitude is buffered to prevent the potentially catastrophic alterations in gene expression that would otherwise occur if NMD were perturbed by environmental or genetic insults. In support of this, here we report the existence of a negative feedback regulatory network that directly acts on seven NMD factors. Feedback regulation is conferred by different branches of the NMD pathway in a cell type-specific and developmentally regulated manner. We identify feedback-regulated NMD factors that are rate limiting for NMD and demonstrate that reversal of feedback regulation in response to NMD perturbation is crucial for maintaining NMD. Together, our results suggest the existence of an intricate feedback network that maintains both RNA surveillance and the homeostasis of normal gene expression in mammalian cells.

Graphical AbstractFigure optionsDownload high-quality image (131 K)Download as PowerPoint slideHighlights▸ A multipronged negative-feedback regulatory pathway that acts on several NMD factors ▸ Functions in a cell type-specific and developmentally regulated manner ▸ Maintains the homeostasis of subsets of normal genes ▸ Serves as a buffering system to maintain RNA quality control in the face of insults