The Long Splice Variant of Ribosomal Protein S24 Protects Cells from Stress and Is Induced by AMPK-ULK1-Regulated Autophagy Independent of mTORC1
TL;DR
This study shows that an allosteric activator of AMPK is sufficient to induce RPS24L and autophagy in normoxia in an ULK1-dependent, but mTORC1-independent manner and interacts with RPS24 mRNA and its autophagy-dependent decrease shifts splicing toward the RPS24L variant.
Abstract
All living organisms have developed complex mechanisms to detect and react to environmental changes to maintain internal balance and support survival. One strategy that cells employ to respond to stress is to refocus the translation machinery to express select stress response proteins, this includes the emerging field of specialized ribosomes. We have previously shown that a long splice variant of ribosomal protein S24 (RPS24L) is induced by several fold in hypoxic monolayers and spheroids in several human cell lines in an autophagy-dependent manner. Here, we show that an allosteric activator of AMPK is sufficient to induce RPS24L and autophagy in normoxia in an ULK1-dependent, but mTORC1-independent manner. Overexpression of RPS24L protected cells from serum starvation and hypoxia, while RPS24 short isoform overexpression during stress impaired autophagy and the ability for cells to survive relative to controls. We show that SRSF1 interacts with RPS24 mRNA and its autophagy-dependent decrease shifts splicing toward the RPS24L variant. This study provides new insights into the signaling and mechanisms that regulate a ribosomal protein splice isoform that protects cells from stress and that has been previously linked to cancer progression.
