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

• Published in: Molecular cell Vol. 69; no. 4; pp. 622 - 635.e6
• Main Authors: Meyer, Cindy, Garzia, Aitor, Mazzola, Michael, Gerstberger, Stefanie, Molina, Henrik, Tuschl, Thomas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.02.2018
• Subjects: alternative splicing; Animalia; apoptosis; binding sites; Cell Cycle; complementary DNA; CRISPR-Cas Systems; Cytoplasmic Granules - metabolism; double-stranded RNA; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; eukaryotic translation initiation factor 2 alpha kinase 2; HEK293 Cells; Humans; integrated stress response; interferon-inducible double-stranded RNA-dependent protein kinase activator A; introns; messenger RNA; phenotype; protein kinases; 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; RNA-Binding Proteins - antagonists & inhibitors; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; stress response; Stress, Physiological; T-Cell Intracellular Antigen-1 - antagonists & inhibitors; T-Cell Intracellular Antigen-1 - genetics; T-Cell Intracellular Antigen-1 - metabolism; T-cell restricted intracellular antigen-1; translation (genetics); Uridine - metabolism; interferon-inducible double-stranded RNA-dependent protein kinase activator A; alternative splicing; eukaryotic translation initiation factor 2 alpha kinase 2; cell cycle; apoptosis; T-cell restricted intracellular antigen-1; integrated stress response
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2018.01.011

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. [Display omitted] •TIA1 proteins are functionally redundant regulators of mRNA stability and splicing•Double knockout of TIA1 and TIAL1 causes mis-splicing of PRKRA mRNA•Loss of PRKRA protein triggers EIF2AK2 activation and stress granule formation•Double knockout of TIA1 and TIAL1 also impairs cell cycle progression Meyer et al. uncover essential contributions of the TIA1 family of RNA-binding proteins for the maturation and translation of target mRNAs by binding to U-rich sequence elements. Loss of TIA1 and TIAL1 function activates RNA-stress-sensing pathways and impairs cell cycle progression.