The TIA1 RNA-Binding Protein Family Regulates EIF2AK2-Mediated Stress Response and Cell Cycle Progression

TIA1 and TIAL1 encode a family of U-rich element mRNA-binding proteins ubiquitously expressed and conserved in metazoans. Using PAR-CLIP, we determined that both proteins bind target sites with identical specificity in 3' UTRs and introns proximal to 5' as well as 3' splice sites. Dou...

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Bibliographic Details
Published in:	Molecular cell Vol. 69; no. 4; p. 622
Main Authors:	Meyer, Cindy, Garzia, Aitor, Mazzola, Michael, Gerstberger, Stefanie, Molina, Henrik, Tuschl, Thomas
Format:	Journal Article
Language:	English
Published:	United States 15.02.2018
Subjects:	Cell Cycle CRISPR-Cas Systems Cytoplasmic Granules - metabolism eIF-2 Kinase - genetics eIF-2 Kinase - metabolism HEK293 Cells Humans Regulatory Sequences, Ribonucleic Acid RNA Splice Sites RNA Splicing RNA, Double-Stranded - genetics RNA, Double-Stranded - metabolism RNA, Messenger - genetics RNA, Messenger - metabolism RNA-Binding Proteins - antagonists & inhibitors RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism Stress, Physiological T-Cell Intracellular Antigen-1 - antagonists & inhibitors T-Cell Intracellular Antigen-1 - genetics T-Cell Intracellular Antigen-1 - metabolism Uridine - metabolism interferon-inducible double-stranded RNA-dependent protein kinase activator A alternative splicing cell cycle eukaryotic translation initiation factor 2 alpha kinase 2 apoptosis T-cell restricted intracellular antigen-1 integrated stress response
ISSN:	1097-4164, 1097-4164
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Summary:	TIA1 and TIAL1 encode a family of U-rich element mRNA-binding proteins ubiquitously expressed and conserved in metazoans. Using PAR-CLIP, we determined that both proteins bind target sites with identical specificity in 3' UTRs and introns proximal to 5' as well as 3' splice sites. Double knockout (DKO) of TIA1 and TIAL1 increased target mRNA abundance proportional to the number of binding sites and also caused accumulation of aberrantly spliced mRNAs, most of which are subject to nonsense-mediated decay. Loss of PRKRA by mis-splicing triggered the activation of the double-stranded RNA (dsRNA)-activated protein kinase EIF2AK2/PKR and stress granule formation. Ectopic expression of PRKRA cDNA or knockout of EIF2AK2 in DKO cells rescued this phenotype. Perturbation of maturation and/or stability of additional targets further compromised cell cycle progression. Our study reveals the essential contributions of the TIA1 protein family to the fidelity of mRNA maturation, translation, and RNA-stress-sensing pathways in human cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4164 1097-4164
DOI:	10.1016/j.molcel.2018.01.011