Translational regulation of chaperone-mediated autophagy by the RNA-binding protein IMP2

During aging, levels of LAMP2A (lysosome-associated membrane protein 2A), a limiting CMA component, decline. Here we show that insulin-like growth factor 2 mRNA-binding protein 2 (IMP2), is a post-transcriptional regulator of CMA that binds Lamp2a mRNA and inhibits its translation, leading to decreased CMA activity and that IMP2 depletion or pharmacological inhibition effectively upregulate CMA.

We identified a fraction of IMP2 at the lysosomal surface and using single-molecule fluorescence in situ hybridization, demonstrated its contribution to the lysosomal degradation of Lamp2a mRNA. IMP2 levels and distribution change with age and in response to dietary lipid challenges, both conditions known to reduce CMA activity. We propose that the increase in IMP2 levels under these conditions enhances Lamp2a RNA degradation, thereby contributing to the decline of CMA.