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Fontaine SN, Zheng D, Sabbagh JJ, Martin MD, Chaput D, Darling A, Trotter JH, Stothert AR, Nordhues BA, Lussier A, Baker J, Shelton L, Kahn M, Blair LJ, Stevens SM Jr, Dickey CA. DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative-associated proteins. EMBO J. 2016 Jul 15;35(14):1537-49. Epub 2016 Jun 3 PubMed.
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Mayo Clinic Florida
This is another interesting paper to help us understand the extracellular release of tau protein from cells. In their report, expressed tau protein appears to be secreted from the cytoplasm in a chaperone complex- and SNAP-dependent manner. Although the majority of the experiments were performed using HEK293T cells, a similar mechanism may be at work in neurons and glia as the authors suggested. This is different from the recent report from Yihong Ye’sgroup, which reported direct secretion of GFP or GFP-tau from the cell in an endoplasmic reticulum-driven manner in HEK293T cells. Thus there appear to be multiple pathways of protein secretion. It is noteworthy that several heat shock protein molecules are consistently detected in exosomes, so it is possible that these also play a role in exosome secretory pathway. One caution is that transient expression of recombinant molecules in HEK293T cells will result in some cytotoxicity, which results in the non-specific release of recombinant molecules. I would like to see more discussion of DnaCJ5 for its clinical relevance to tauopathy, which is missing in the discussion. Overall these are carefully performed experiments in mostly non-neuronal cell lines and would require future validation in more physiological conditions.
View all comments by Tsuneya IkezuThe study by Fontaine et al. reports an unconventional protein secretion mechanism that eliminates misfolded proteins from the cytosol. Intriguingly, several neurodegenerative disease-associated aberrant proteins, such as tau and α-synuclein, can be released into the cell exterior through this mechanism. This was observed in regular 293T cells as well as in neurons. It has been postulated previously that tau protein might exit the cell using an exosome-mediated unconventional protein secretion pathway, although this model lacks supporting evidence. By contrast, the authors here present strong evidence, demonstrating that most tau and α-synuclein are actually released from the cell by a pathway distinct from exosome-mediated secretion, and that it depends on the cytosolic heat shock protein Hsc70, its co-chaperone DnaJC5, and a SNARE protein. These results suggest the possibility that misfolded cargo proteins are initially recruited by the chaperone and then use a vesicle intermediate to exit the cell. Although the authors did not know exactly what kind of vesicle intermediate carries out this function, or the precise identity of this pathway, the working hypothesis proposed (Fig. 4) is surprisingly similar to the model reached by our recent study, published in Nature Cell Biology (Lee et al., 2016). In our study, we reported a pathway named MAPS that is dedicated for exporting misfolded proteins including α-synuclein from the cell. This pathway uses the ER-associated chaperone/deubiquitinase USP19 to recruit misfolded proteins to the ER surface, putting them into late endosomes that are parked on the ER for secretion. Although the experimental conditions used in these two studies are different (Fontaine et al. used serum-free medium to grow cells while analyzing secretion, whereas we used complete medium), it is very likely that Fontaine and colleagues are dealing with the same pathway as MAPS. If so, it would be interesting to dissect the functional interplays between USP19 and Hsc70 in this novel and intriguing protein quality control pathway.
References:
Lee JG, Takahama S, Zhang G, Tomarev SI, Ye Y. Unconventional secretion of misfolded proteins promotes adaptation to proteasome dysfunction in mammalian cells. Nat Cell Biol. 2016 Jun 13; PubMed.
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