TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau
| Autor: | Muhammet M Öztürk, Bryce L Mashimo, Maria Medalla, Lulu Jiang, Samantha Boudeau, Peter E.A. Ash, Guillermo Socorro, Jenifer Shattuck, Susanne Wegmann, Pavel Ivanov, Yari Carlomagno, Nicholas M. Kanaan, Benjamin Wolozin, Mark Knobel, Leonard Petrucelli, Shuwen Lei, Louloua F A Al-Mohanna |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
metabolism [T-Cell Intracellular Antigen-1]
Amyloid TIA1 Tau protein metabolism [RNA Recognition Motif Proteins] RNA-binding protein tau Proteins metabolism [Neurodegenerative Diseases] Fibril Protein Aggregation Pathological etiology [Neurodegenerative Diseases] Protein Aggregates Stress granule chemistry [RNA Recognition Motif Proteins] mental disorders Organelle chemistry [Amyloid] Humans fibrillar tau Protein Interaction Domains and Motifs oligomeric tau metabolism [Amyloid] Neurons Multidisciplinary biology Chemistry chemistry [tau Proteins] pathology [Neurodegenerative Diseases] RNA Neurodegenerative Diseases Biological Sciences Alzheimer's disease In vitro metabolism [tau Proteins] Recombinant Proteins T-Cell Intracellular Antigen-1 RNA Recognition Motif Proteins metabolism [Neurons] biology.protein Biophysics liquid–liquid phase separation (LLPS) ddc:500 RNA binding proteins Protein Multimerization Neuroscience Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America 118(9), e2014188118-(2021). doi:10.1073/pnas.2014188118 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2014188118 |
| Popis: | Significance Phase separation of proteins is increasingly thought to play a fundamental role in biological processes. Recent studies show that tau protein phase separates, but the biological significance is unknown since artificial crowding agents are typically used and the resulting tau is not toxic. We now demonstrate that TIA1 potentiates RNA-mediated phase separation of tau, thereby enabling a process that occurs at physiological concentrations and also directs the formation of biologically active, highly neurotoxic oligomeric tau. Coordinated phase separation of functionally related proteins provides a general mechanism through which membraneless organelles can direct biological activities. Tau protein plays an important role in the biology of stress granules and in the stress response of neurons, but the nature of these biochemical interactions is not known. Here we show that the interaction of tau with RNA and the RNA binding protein TIA1 is sufficient to drive phase separation of tau at physiological concentrations, without the requirement for artificial crowding agents such as polyethylene glycol (PEG). We further show that phase separation of tau in the presence of RNA and TIA1 generates abundant tau oligomers. Prior studies indicate that recombinant tau readily forms oligomers and fibrils in vitro in the presence of polyanionic agents, including RNA, but the resulting tau aggregates are not particularly toxic. We discover that tau oligomers generated during copartitioning with TIA1 are significantly more toxic than tau aggregates generated by incubation with RNA alone or phase-separated tau complexes generated by incubation with artificial crowding agents. This pathway identifies a potentially important source for generation of toxic tau oligomers in tau-related neurodegenerative diseases. Our results also reveal a general principle that phase-separated RBP droplets provide a vehicle for coassortment of selected proteins. Tau selectively copartitions with TIA1 under physiological conditions, emphasizing the importance of TIA1 for tau biology. Other RBPs, such as G3BP1, are able to copartition with tau, but this happens only in the presence of crowding agents. This type of selective mixing might provide a basis through which membraneless organelles bring together functionally relevant proteins to promote particular biological activities. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|