TIA-1 Is a Functional Prion-Like Protein

Abstract

Prions are self-propagating protein conformations that are traditionally regarded as agents of neurodegenerative disease in animals. However, it has become evident that prion-like aggregation of endogenous proteins can also occur under normal physiological conditions (e.g., during memory storage or activation of the immune response). In this review, we focus on the functional prion-related protein TIA-1, an RNA-binding protein that is involved in multiple aspects of RNA metabolism but is best understood in terms of its role in stress granule assembly during the cellular stress response. We propose that stress granule formation provides a useful conceptual framework with which to address the positive role of TIA-1 prion-like aggregation. Elucidating the function of TIA-1 prion-like aggregation will advance our understanding of how prion-based molecular switches are used in normal physiological settings.

Figure 1.

(A) In cultured mouse hippocampal neurons, endogenous T-cell intracellular antigen-1 (TIA-1) is diffusely present in both the nucleus and cytoplasm, with more prominent staining in the nucleus. Upon brief treatment with sodium arsenite, a potent oxidant, TIA-1 protein dramatically relocalizes into cytoplasmic foci known as stress granules (indicated by arrows). (B) Mammalian TIA-1 contains three RNA-binding domains (RRMs) and a C-terminal prion-related domain. (C) The C-terminal prion-related domain of mouse TIA-1 is highly enriched in the polar amino acids asparagine and glutamine.

Figure 2.

(A) Prions arise from the spontaneous conversion of a soluble protein conformation into an aggregated, self-propagating form that is cytotoxic and causes neurodegenerative disease. (B) In contrast to pathogenic prions, functional prion-like proteins undergo physiologically regulated conversion from soluble to aggregated forms that are likely to contribute in multiple ways to normal biological processes, including viral immunity, development, and cellular homeostasis.

Figure 3.

(A) Overexpression of yellow fluorescent protein (YFP)-tagged mouse TIA-1 in yeast leads to the formation of stress granule–like structures. In contrast, YFP alone does not produce such structures. (B) TIA-1-YFP forms high-molecular-weight (m.w.) aggregates that are sodium dodecyl sulfate (SDS)-resistant, as observed by SDS-agarose gel electrophoresis. Boiling the extracts causes the collapse of aggregated protein into monomer. (C) Formation of mouse TIA-1 aggregates in a heterologous yeast assay occurs more rapidly in yeast cultures that have been previously induced to express the protein (INI), compared with a culture that is freshly induced in parallel (NNI). No TIA-1 aggregates are observed during the “no induction” phase of INI cultures. The seeding effect is observed at both 10 and 20 h after reinduction (INI) of TIA-1.