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PMID: 15371533 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Stress granule assembly is mediated by prion-like aggregation of TIA-1.

Molecular biology of the cell ·Vol. 15 ·No. 12 ·2004-12-00 ·Pages 5383-98

Gilks N, Kedersha N, Ayodele M, Shen L, Stoecklin G, Dember LM, Anderson P

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.

MeSH Terms
Amino Acid Sequence Animals COS Cells Chlorocebus aethiops Cytoplasmic Granules/metabolism Gene Expression Regulation HSP70 Heat-Shock Proteins/genetics,metabolism Humans Inclusion Bodies/metabolism Mice Microscopy, Electron, Transmission Molecular Sequence Data Peptide Hydrolases/metabolism Prions/chemistry Protein Binding RNA-Binding Proteins/chemistry,genetics,metabolism Ribosomes/metabolism Solubility
Chemicals
HSP70 Heat-Shock Proteins Prions RNA-Binding Proteins Tial1 protein, mouse Peptide Hydrolases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Gilks Natalie
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA.
Kedersha Nancy
Ayodele Maranatha
Shen Lily
Stoecklin Georg
Dember Laura M
Anderson Paul
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.e04-08-0715
Published
2004-12-00
Epub
2004-00-15
Pages
5383-98
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC532018
Subset
IM
Grants
NIAID NIH HHS · R56 AI033600 · United States
NIAID NIH HHS · R01 AI033600 · United States
NIAID NIH HHS · AI33600 · United States
NIAID NIH HHS · R01 AI050167 · United States
NIAID NIH HHS · AI50167 · United States
External Links
PubMed source DOI: 10.1091/mbc.e04-08-0715 PMC Full Text View journal details
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