title: Stress granule assembly is mediated by prion-like aggregation of TIA-1.
abstract: TIA-1 is an RNA binding protein that promotes the assembly of stress granules (SGs), discrete cytoplasmic inclusions into which stalled translation initiation complexes are dynamically recruited in cells subjected to environmental stress. The RNA recognition motifs of TIA-1 are linked to a glutamine-rich prion-related domain (PRD). Truncation mutants lacking the PRD domain do not induce spontaneous SGs and are not recruited to arsenite-induced SGs, whereas the PRD forms aggregates that are recruited to SGs in low-level-expressing cells but prevent SG assembly in high-level-expressing cells. The PRD of TIA-1 exhibits many characteristics of prions: concentration-dependent aggregation that is inhibited by the molecular chaperone heat shock protein (HSP)70; resistance to protease digestion; sequestration of HSP27, HSP40, and HSP70; and induction of HSP70, a feedback regulator of PRD disaggregation. Substitution of the PRD with the aggregation domain of a yeast prion, SUP35-NM, reconstitutes SG assembly, confirming that a prion domain can mediate the assembly of SGs. Mouse embryomic fibroblasts (MEFs) lacking TIA-1 exhibit impaired ability to form SGs, although they exhibit normal phosphorylation of eukaryotic initiation factor (eIF)2alpha in response to arsenite. Our results reveal that prion-like aggregation of TIA-1 regulates SG formation downstream of eIF2alpha phosphorylation in response to stress.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Gilks
authors.forename: Nancy
authors.initials: N
authors.lastname: Kedersha
authors.forename: Maranatha
authors.initials: M
authors.lastname: Ayodele
authors.forename: Lily
authors.initials: L
authors.lastname: Shen
authors.forename: Georg
authors.initials: G
authors.lastname: Stoecklin
authors.forename: Laura M
authors.initials: LM
authors.lastname: Dember
authors.forename: Paul
authors.initials: P
authors.lastname: Anderson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003594:Cytoplasmic Granules / Q000378:metabolism*; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000378:metabolism; D011328:Prions / Q000737:chemistry*; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism; D012995:Solubility
chemical_list: D018840:HSP70 Heat-Shock Proteins; D011328:Prions; D016601:RNA-Binding Proteins; C489665:Tial1 protein, mouse; D010447:Peptide Hydrolases