Translational tolerance of mitochondrial genes to metabolic energy stress involves TISU and eIF1-eIF4GI cooperation in start codon selection.
Protein synthesis is a major energy-consuming process, which is rapidly repressed upon energy stress by AMPK. How energy deficiency affects translation of mRNAs that cope with the stress response is poorly understood. We found that mitochondrial genes remain translationally active upon energy deprivation. Surprisingly, inhibition of translation is partially retained in AMPKα1/AMPKα2 knockout cells. Mitochondrial mRNAs are enriched with TISU, a translation initiator of short 5' UTR, which confers resistance specifically to energy stress. Purified 48S preinitiation complex is sufficient for initiation via TISU AUG, when preceded by a short 5' UTR. eIF1 stimulates TISU but inhibits non-TISU-directed initiation. Remarkably, eIF4GI shares this activity and also interacts with eIF1. Furthermore, eIF4F is released upon 48S formation on TISU. These findings describe a specialized translation tolerance mechanism enabling continuous translation of TISU genes under energy stress and reveal that a key step in start codon selection of short 5' UTR is eIF4F release.
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.
Hadar
H
Sinvani
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.
Ora
O
Haimov
Department of Biochemistry and Goodman Cancer Centre, McGill University, Montreal, QC H3A 1A3, Canada.
Yuri
Y
Svitkin
Department of Biochemistry and Goodman Cancer Centre, McGill University, Montreal, QC H3A 1A3, Canada.
Nahum
N
Sonenberg
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.
Ana
A
Tamarkin-Ben-Harush
University Paris Descartes, Institut Cochin, 75014 Paris, France.
Benoit
B
Viollet
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: rivka.dikstein@weizmann.ac.il.
Rivka
R
Dikstein
D055372:AMP-Activated Protein Kinases / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D018387:Codon, Initiator / Q000235:genetics*; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics*; D039642:Eukaryotic Initiation Factors / Q000235:genetics*; D050259:Genes, Mitochondrial / Q000235:genetics*; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D014176:Protein Biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D000077278:RNA, Mitochondrial; D012270:Ribosomes / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics*
D018387:Codon, Initiator; C410108:EIF1 protein, human; C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G; D039642:Eukaryotic Initiation Factors; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000077278:RNA, Mitochondrial; C029305:mitochondrial messenger RNA; C526222:PRKAG1 protein, human; C526223:PRKAG2 protein, human; D055372:AMP-Activated Protein Kinases