L13a blocks 48S assembly: role of a general initiation factor in mRNA-specific translational control.
Transcript-specific translational control restricts macrophage inflammatory gene expression. The proinflammatory cytokine interferon-gamma induces phosphorylation of ribosomal protein L13a and translocation from the 60S ribosomal subunit to the interferon-gamma-activated inhibitor of translation (GAIT) complex. This complex binds the 3'UTR of ceruloplasmin mRNA and blocks its translation. Here, we elucidate the molecular mechanism underlying repression by L13a. Translation of the GAIT element-containing reporter mRNA is sensitive to L13a-mediated silencing when driven by internal ribosome entry sites (IRESs) that require initiation factor eIF4G, but is resistant to silencing when driven by eIF4F-independent IRESs, demonstrating a critical role for eIF4G. Interaction of L13a with eIF4G blocks 43S recruitment without suppressing eIF4F complex formation. eIF4G attack, e.g., by virus, stress, or caspases, is a well-known mechanism of global inhibition of protein synthesis. However, our studies reveal a unique mechanism in which targeting of eIF4G by mRNA-bound L13a elicits transcript-specific translational repression.
Kapasi
Purvi
P
Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA.
Chaudhuri
Sujan
S
Vyas
Keyur
K
Baus
Diane
D
Komar
Anton A
AA
Fox
Paul L
PL
Merrick
William C
WC
Mazumder
Barsanjit
B
D001665:Binding Sites; D039621:Eukaryotic Initiation Factor-3 / Q000378:metabolism; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000737:chemistry / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D008957:Models, Genetic; D010448:Peptide Initiation Factors / Q000378:metabolism*; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D012315:RNA Caps / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D012269:Ribosomal Proteins / Q000378:metabolism*; D012270:Ribosomes / Q000737:chemistry* / Q000378:metabolism*
D039621:Eukaryotic Initiation Factor-3; D039562:Eukaryotic Initiation Factor-4F; D039603:Eukaryotic Initiation Factor-4G; D010448:Peptide Initiation Factors; D012315:RNA Caps; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins