title: Translational coregulation of 5'TOP mRNAs by TIA-1 and TIAR.
abstract: The response of cells to changes in their environment often requires coregulation of gene networks, but little is known about how this can occur at the post-transcriptional level. An important example of post-transcriptional coregulation is the selective translational regulation in response to growth conditions of mammalian mRNAs that encode protein biosynthesis factors and contain hallmark 5'-terminal oligopyrimidine tracts (5'TOP). However, the responsible trans-factors and the mechanism by which they coregulate 5'TOP mRNAs have remained elusive. Here we identify stress granule-associated TIA-1 and TIAR proteins as key factors in human 5'TOP mRNA regulation, which upon amino acid starvation assemble onto the 5' end of 5'TOP mRNAs and arrest translation at the initiation step, as evidenced by TIA-1/TIAR-dependent 5'TOP mRNA translation repression, polysome release, and accumulation in stress granules. This requires starvation-mediated activation of the GCN2 (general control nonderepressible 2) kinase and inactivation of the mTOR (mammalian target of rapamycin) signaling pathway. Our findings provide a mechanistic explanation to the long-standing question of how the network of 5'TOP mRNAs are coregulated according to amino acid availability, thereby allowing redirection of limited resources to mount a nutrient deprivation response. This presents a fundamental example of how a group of mRNAs can be translationally coregulated in response to changes in the cellular environment.
authors: Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA. cd@mb.au.dk
authors: Christian Kroun
authors: CK
authors: Damgaard
authors: Jens
authors: J
authors: Lykke-Andersen
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D039102:Poly(A)-Binding Proteins / Q000378:metabolism*; D011132:Polyribosomes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D038641:RNA 5' Terminal Oligopyrimidine Sequence / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D000074019:T-Cell Intracellular Antigen-1
chemical_list: D000596:Amino Acids; D039102:Poly(A)-Binding Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; C076751:TIAL1 protein, human; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases