The balance between protein anabolism and catabolism sets the foundations on which cells build their homeostasis. RACK1 is a ribosome-associated scaffold protein involved in signal transduction. On the ribosome, RACK1 enhances specific translation. Conversely, upon growth factor/nutrient starvation, RACK1 is present in a ribosome-free form and inhibits protein synthesis. However, the precise role of RACK1 when not bound to the ribosome still requires elucidation. Here, we show that extra-ribosomal RACK1 increases LC3-II accumulation, thereby mimicking an autophagy-like phenotype. Next, based on the ribosome-bound structure of RACK1, we suggest a possible mechanism for RACK1 release from the ribosome which relie... More
The balance between protein anabolism and catabolism sets the foundations on which cells build their homeostasis. RACK1 is a ribosome-associated scaffold protein involved in signal transduction. On the ribosome, RACK1 enhances specific translation. Conversely, upon growth factor/nutrient starvation, RACK1 is present in a ribosome-free form and inhibits protein synthesis. However, the precise role of RACK1 when not bound to the ribosome still requires elucidation. Here, we show that extra-ribosomal RACK1 increases LC3-II accumulation, thereby mimicking an autophagy-like phenotype. Next, based on the ribosome-bound structure of RACK1, we suggest a possible mechanism for RACK1 release from the ribosome which relies on phosphorylation of precise amino acid residues, namely Thr39, Ser63, Thr86, Ser276, Thr277, Ser278, Ser279. Specifically, by performing an unbiased in silico screening using phospho-kinase prediction tools, we propose that, upon starving, AMPK1/2, ULK1/2 and PKR are the strongest candidate protein kinases to phosphorylate RACK1. This may be relevant in the context of caloric restriction and cancer therapy, where repressing translation of specific mRNAs would open important therapeutic avenues. Overall, our work provides novel insight into RACK1 function(s) by connecting its ribosomal and extra-ribosomal activities with translation and signaling.
