The progressive deposition of misfolded hyperphosphorylated tau is a pathological hallmark of tauopathies, including Alzheimer's disease. However, the underlying molecular mechanisms governing the intercellular spreading of tau species remain elusive. Here, we show that full-length soluble tau is unconventionally secreted by direct translocation across the plasma membrane. Increased secretion is favored by tau hyperphosphorylation, which provokes microtubule detachment and increases the availability of free protein inside cells. Using a series of binding assays, we show that free tau interacts with components enriched at the inner leaflet of the plasma membrane, finally leading to its translocation across the plasma membrane mediated by sulfated proteoglycans. We provide further evidence that secreted soluble tau species spread trans-cellularly and are sufficient for the induction of intracellular tau aggregation in adjacent cells. Our study demonstrates the mechanistic details of tau secretion and provides insights into the initiation and progression of tau pathology.
A big surprise in the molecular cell biology of eukaryotes has been the discovery of pathways of protein secretion that are not linked to the endoplasmic reticulum (ER) and the Golgi apparatus. Various kinds of unconventional secretory processes have been described, including two major pathways for two distinct sets of cargoes that are initially synthesized as soluble proteins in the cytoplasm. These two pathways are mechanistically distinct from one another. One is based upon direct protein translocation across lipidic pores in the plasma membrane (type I unconventional secretion). The second pathway involves the recruitment of cytoplasmic proteins into vesicular compartments of the endocytic membrane system that fuse with the plasma membrane to release proteins into the extracellular space (type III unconventional secretion). This primer highlights the mechanisms and molecular machineries of these pathways that were discovered with fibroblast growth factor 2 (FGF2; type I) and acyl-CoA binding protein (Acb1; type III) as the most prominent cargo proteins. Furthermore, the physiological significance of these secretory routes in both health and disease is discussed for a broader range of cargo proteins.
Background: FGF2 translocation across plasma membranes depends on phosphoinositide-dependent oligomerization and membrane pore formation. Results: Two unique surface cysteines are critical for efficient FGF2 oligomerization, membrane pore formation, and FGF2 secretion from cells. Conclusion: Formation of intermolecular disulfide bridges drives phosphoinositide-dependent FGF2 oligomerization at plasma membranes. Significance: A new cis element critical for unconventional secretion of FGF2 was identified and validated.
FGF2 is exported from cells by an unconventional secretory mechanism. Here, we directly visualized individual FGF2 membrane translocation events at the plasma membrane using live cell TIRF microscopy. This process was dependent on both PI(4,5)P2–mediated recruitment of FGF2 at the inner leaflet and heparan sulfates capturing FGF2 at the outer plasma membrane leaflet. By simultaneous imaging of both FGF2 membrane recruitment and the appearance of FGF2 at the cell surface, we revealed the kinetics of FGF2 membrane translocation in living cells with an average duration of ∼200 ms. Furthermore, we directly demonstrated FGF2 oligomers at the inner leaflet of living cells with a FGF2 dimer being the most prominent species. We propose this dimer to represent a key intermediate in the formation of higher FGF2 oligomers that form membrane pores and put forward a kinetic model explaining the mechanism by which membrane-inserted FGF2 oligomers serve as dynamic translocation intermediates during unconventional secretion of FGF2.
Background: Unconventional secretion of FGF2 occurs by direct translocation across plasma membranes. Results: The cytoplasmic domain of ATP1A1 directly interacts with FGF2 and is required for FGF2 secretion. Conclusion: ATP1A1 supports unconventional secretion by recruiting FGF2 to the inner leaflet of plasma membranes. Significance: A new machinery component required for unconventional secretion of FGF2 was identified and validated.
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