Universität zu Köln 

Prof. Dr. Jörg Höhfeld

Institut für Zellbiologie, Universität Bonn
email: hoehfeld@uni-bonn.de
phone: +49-(0)228 735 308
website

Our work over the last years revealed chaperone-assisted protein degradation as an essential proteostasis mechanism in higher eukaryotes. Using transgenic flies and mice unable to express certain Hsc70-regulating co-chaperones, chaperone-assisted degradation was found to be essential for muscle maintenance and to control male germ cell development. BAG-domain co-chaperones emerged as central regulators of chaperone-assisted degradation, with BAG-1 triggering a proteasomal degradation pathway and BAG-3 initiating chaperone-assisted selective autophagy (CASA). We will now investigate the molecular mechanisms underlying the BAG-1/BAG-3-mediated switch between proteasomal and autophagic degradation. The physiological importance of restricting chaperone-assisted degradation will be explored through the further functional characterisation of the co-chaperones BAG-2 and HspBP1, which both inhibit the chaperone-associated ubiquitin ligase CHIP, and of BAG-5 that abrogates the activity of Parkin, another ubiquitin ligase associated with Hsc/Hsp70. Characterisation will include the generation of a BAG-5-deficient mouse strain to determine the role of this co-chaperone at the organismal level. Finally, transgenic RNAi flies will be employed for the stage- and tissue-specific ablation of degradation-regulating co-chaperones. The combination of the different approaches will provide insights into proteostasis mechanisms that balance chaperone-mediated folding and chaperone-assisted proteasomal and autophagic degradation, and will unravel the importance of these processes for tissue development and maintenance.

Running time: 07/2003 – 06/2015

Recent publications:

Ulbricht, A., Gehlert, S., Leciejewski, B., Schiffer, T., Bloch, W., and Höhfeld, J. (2015). Induction and adaptation of chaperone-assisted selective autophagy CASA in response to resistance exercise in human skeletal muscle. Autophagy 11, 1-9. PubMed

Ulbricht, A., Arndt, V., and Höhfeld, J. (2013a). Chaperone-assisted proteostasis is essential for mechanotransduction in mammalian cells. Commun Integr Biol 6, e24925. PubMed

Ulbricht, A., Eppler, F.J., Tapia, V.E., van der Ven, P.F., Hampe, N., Hersch, N., Vakeel, P., Stadel, D., Haas, A., Saftig, P., Behrends, C., Fürst, D. O., Volkmer, R., Hoffmann, B., Kolanus, W., and Höhfeld, J. (2013b). Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy. Curr Biol 23, 430-435. PubMed

Ulbricht, A., and Höhfeld, J. (2013). Tension-induced autophagy: may the chaperone be with you. Autophagy 9, 920-922. PubMed

Dreiseidler, M., Dick, N. and Höhfeld, J. (2012). Analysis of chaperone-assisted ubiquitylation. Methods Mol Biol 832, 473-487. PubMed

Gaude, H., Aznar, N., Delay, A., Bres, A., Buchet-Poyau, K., Caillat, C., Vigouroux, A., Rogon, C., Woods, A., Vanacker, J. M., Höhfeld, J., Perret, C., Meyer, P., Billaud, M. and Forcet, C. (2012). Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1. Oncogene 31, 1582-1591. PubMed

Kettern, N., Rogon, C., Limmer, A., Schild, H., and Höhfeld, J. (2011). The Hsc/Hsp70 co-chaperone network controls antigen aggregation and presentation during maturation of professional antigen presenting cells. PLoS One. 6 (1), e16398.

Okiyoneda, T., Barriere, H., Bagdany, M., Rabeh, W.M., Du, K., Höhfeld, J., Young, J.C., and Lukacs, G.L. (2010). Peripheral protein quality control removes unfolded CFTR from the plasma membrane. Science 329, 805-810.

Löffek, S., Woll, S., Höhfeld, J., Leube, R.E., Has, C., Bruckner-Tüderman, L., and Magin, T.M. (2010). The ubiquitin ligase CHIP/STUB1 targets mutant keratins for degradation. Hum. Mutat. 31, 466-476.

Arndt, V., Dick, N., Tawo, R., Dreiseidler, M., Wenzel, D., Hesse, M., Fürst, D.O., Saftig, P., Saint, R., Fleischmann, B.K., Hoch, M., and Höhfeld, J. (2010). Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr. Biol. 20, 143-148.

Kettern, N., Dreiseidler, M., Tawo, R., and Höhfeld, J. (2010). Chaperone-assisted degradation: multiple paths to destruction. Biol. Chem. 391, 481-489. (review)

Spooner, R.A., Hart, P.J., Cook, J.P., Pietroni, P., Rogon, C., Höhfeld, J., Roberts, L.M., and Lord, J.M. (2008). Cytosolic chaperones influence the fate of a toxin dislocated from the endoplasmic reticulum. Proc. Natl. Acad. Sci. U.S.A. 105, 17408-17413.

Arndt, V., Rogon, C., and Höhfeld, J. (2007). To be, or not to be--molecular chaperones in protein degradation. Cell. Mol. Life Sci. 64, 2525-2541. (review)

Westhoff, B., Chapple, J.P., van der Spuy, J., Höhfeld, J., and Cheetham, M.E. (2005). HSJ1 is a neuronal shuttling factor for the sorting of chaperone clients to the proteasome. Curr. Biol. 15, 1058-1064.