Activities of Ligatin and MCT-1/DENR in eukaryotic translation initiation and ribosomal recycling.
Eukaryotic translation initiation begins with ribosomal recruitment of aminoacylated initiator tRNA (Met-tRNA(Met)(i)) by eukaryotic initiation factor eIF2. In cooperation with eIF3, eIF1, and eIF1A, Met-tRNA(Met)(i)/eIF2/GTP binds to 40S subunits yielding 43S preinitiation complexes that attach to the 5'-terminal region of mRNAs and then scan to the initiation codon to form 48S initiation complexes with established codon-anticodon base-pairing. Stress-activated phosphorylation of eIF2alpha reduces the level of active eIF2, globally inhibiting translation. However, translation of several viral mRNAs, including Sindbis virus (SV) 26S mRNA and mRNAs containing hepatitis C virus (HCV)-like IRESs, is wholly or partially resistant to inhibition by eIF2 phosphorylation, despite requiring Met-tRNA(Met)(i). Here we report the identification of related proteins that individually (Ligatin) or together (the oncogene MCT-1 and DENR, which are homologous to N-terminal and C-terminal regions of Ligatin, respectively) promote efficient eIF2-independent recruitment of Met-tRNA(Met)(i) to 40S/mRNA complexes, if attachment of 40S subunits to the mRNA places the initiation codon directly in the P site, as on HCV-like IRESs and, as we show here, SV 26S mRNA. In addition to their role in initiation, Ligatin and MCT-1/DENR can promote release of deacylated tRNA and mRNA from recycled 40S subunits after ABCE1-mediated dissociation of post-termination ribosomes.
Skabkin
Maxim A
MA
Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA.
Skabkina
Olga V
OV
Dhote
Vidya
V
Komar
Anton A
AA
Hellen
Christopher U T
CU
Pestova
Tatyana V
TV
D000818:Animals; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D016174:Hepacivirus / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012343:RNA, Transfer / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D011817:Rabbits; D054682:Ribosome Subunits, Small, Eukaryotic / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D012845:Sindbis Virus / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
D039642:Eukaryotic Initiation Factors; D008565:Membrane Proteins; D027501:Monocarboxylic Acid Transporters; D012333:RNA, Messenger; D012367:RNA, Viral; D014764:Viral Proteins; C013090:ligatin; D012343:RNA, Transfer