Autophagy ‐dependent alternative splicing of ribosomal protein S24 produces a more stable isoform that aids in hypoxic cell survival

Hypoxic human cells increase the abundance of a longer mRNA splice variant of ribosomal protein S24 (RPS24L) by retaining a 22  bp cassette exon. RPS24L is induced in an autophagy-dependent manner, while the shorter variant RPS24S is reduced by mTORC1 repression in a hypoxia-inducible factor-dependent manner. RPS24L produces a more stable protein isoform that aids in hypoxic cell survival. Cells remodel splicing and translation machineries to mount specialized gene expression responses to stress. Here, we show that hypoxic human cells in 2D and 3D culture models increase the relative abundance of a longer mRNA variant of ribosomal protein S24 (RPS24L) compared to a shorter mRNA variant (RPS24S) by favoring the inclusion of a 22  bp cassette exon. Mechanistically, RPS24L and RPS24S are induced and repressed, respectively, by distinct pathways in hypoxia: RPS24L is induced in an autophagy-dependent manner, while RPS24S is reduced by mTORC1 repression in a hypoxia-inducible factor-dependent manner. RPS24L produces a more st able protein isoform that aids in hypoxic cell survival and growth, which could be exploited by cancer cells in the tumor microenvironment.
Source: FEBS Letters - Category: Biochemistry Authors: Tags: Research Article Source Type: research