Translational control of the cytosolic stress response by mitochondrial ribosomal protein L18

In response to stress, cells attenuate global protein synthesis but permit efficient translation of mRNAs encoding heat shock proteins (HSPs). Despite decades since the first description of the heat shock response, how cells achieve translational control of HSP synthesis remains enigmatic. Here we report an unexpected role for mitochondrial ribosomal protein L18 (MRPL18) in the mammalian cytosolic stress response. MRPL18 bears a downstream CUG start codon and generates a cytosolic isoform in a stress-dependent manner. Cytosolic MRPL18 incorporates into the 80S ribosome and facilitates ribosome engagement on mRNAs selected for translation during stress. MRPL18 knockdown has minimal effects on mitochondria function, but substantially dampens cytosolic HSP expression at the level of translation. Our results uncover a hitherto uncharacterized stress adaptation mechanism in mammalian cells, which involves formation of a “hybrid” ribosome responsible for translational regulation during the cytosolic stress response.