A non-canonical role for HIF-1α: redirecting DGCR8 to the RNA exosome for snoRNA degradation and translational modulation.

The RNA exosome complex (EC) is a multi-protein complex responsible for RNA surveillance. Guided by specific adaptor factors, the EC recognizes RNA species as substrates for processing or degradation. Although its basic structure and components are documented, the regulatory mechanisms that enable this fundamental machinery to respond to biological signals remain unclear. Here, we demonstrate that hypoxia-inducible factor 1-alpha (HIF-1α) brings DGCR8 to associate with the EC in an RNA-independent manner and shifts DGCR8's RNA-binding preference toward small nucleolar RNAs (snoRNAs). This circuit triggers the snoRNA degradation without affecting their transcription or processing, ultimately impairing ribosomal RNA (rRNA) modifications such as pseudouridylation and 2'-O-methylation, compromising rRNA processing, and reducing global translation efficiency. The HIF-1α-mediated reconfiguration of DGCR8 with EC involves the release of DGCR8 and RRP6 from the nucleoli to the nucleoplasm and is conserved across multiple species, including worms and flies. Under conditions where HIF-1α is induced, we found that the MC-to-EC switch dynamically responds to hypoxic conditions and growth factor signals. In conclusion, the discovery of MC-to-EC switch reveals a multifaceted function of HIF-1α in noncoding RNA regulation, also emphasizing its non-transcriptional impact on the DGCR8-EC-mediated snoRNA degradation pathway and its consequential effects on rRNA modifications and translation, providing new insights into RNA homeostasis regulation.