Screening of small molecules affecting mammalian P-body assembly uncovers links with diverse intracellular processes and organelle physiology

Abstract

Processing bodies (P-bodies) are cytoplasmatic mRNP granules containing non-translating mRNAs and proteins from the mRNA decay and silencing machineries. The mechanism of P-body assembly has been typically addressed by depleting P-body components. Here we apply a complementary approach and establish an automated cell-based assay platform to screen for molecules affecting P-body assembly. From a unique library of compounds derived from myxobacteria, 30 specifically inhibited P-body assembly. Gephyronic acid A (GA), a eukaryotic protein synthesis inhibitor, showed the strongest effect. GA also inhibited, under stress conditions, phosphorylation of eIF2α and stress granule formation. Other hits uncovered interesting novel links between P-body assembly, lipid metabolism, and internal organelle physiology. The obtained results provide a chemical toolbox to manipulate P-body assembly and function.

Keywords: :

• P-body assembly
• eIF2α
• gephyronic acid A
• inhibitors
• myxobacterial metabolites
• processing bodies
• stress granules

10.4161/rna.26851

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This work was supported by the Spanish Ministerio de Ciencia e Innovación (grants BFU2010-20803 and SAF2020-21336) and Deutsche Forschungsgemeinschaft SA 356/7-1.