Abstract
Disturbances in proteostasis are observed in many neurodegenerative diseases. This leads to activation of protein quality control to restore proteostasis, with a key role for the removal of aberrant proteins by proteolysis. The unfolded protein response (UPR) is a protein quality control mechanism of the endoplasmic reticulum (ER) that is activated in several neurodegenerative diseases. Recently we showed that the major proteolytic pathway during UPR activation is via the autophagy/lysosomal system. Here we investigate UPR induction if the other major proteolytic pathway of the ER -ER associated degradation (ERAD)-is inhibited. Surprisingly, impairment of ERAD results in decreased UPR activation and protects against ER stress toxicity. Autophagy induction is not affected under these conditions, however, a striking relocalization of the lysosomes is observed. Our data suggest that a protective UPR-modulating mechanism is activated if ERAD is inhibited, which involves lysosomes. Our data provide insight in the cross-talk between proteolytic pathways involved in ER proteostasis. This has implications for neurodegenerative diseases like Alzheimer’s disease where disturbed ER proteostasis and proteolytic impairment are early phenomena in the pathology.
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Avezov, E., Frenkel, Z., Ehrlich, M., Herscovics, A., and Lederkremer, G.Z. (2008). Endoplasmic reticulum (ER) mannosidase I is compartmentalized and required for N-glycan trimming to Man5-6GlcNAc2 in glycoprotein ER-associated degradation. Mol. Biol. Cell 19, 216–225.
Balch, W.E., Morimoto, R.I., Dillin, A., and Kelly, J.W. (2008). Adapting proteostasis for disease intervention. Science 319, 916–919.
Bernales, S., McDonald, K.L., and Walter, P. (2006). Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 4, e423.
Bernales, S., Schuck, S., and Walter, P. (2007). ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy 3, 285–287.
Cali, T., Galli, C., Olivari, S., and Molinari, M. (2008). Segregation and rapid turnover of EDEM1 by an autophagy-like mechanism modulates standard ERAD and folding activities. Biochem. Biophys. Res. Commun. 371, 405–410.
Ding, W.X., Ni, H.M., Gao, W., Hou, Y.F., Melan, M.A., Chen, X., Stolz, D.B., Shao, Z.M., and Yin, X.M. (2007). Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J. Biol. Chem. 282, 4702–4710.
Elfrink, H.L., Zwart, R., Cavanillas, M.L., Schindler, A.J., Baas, F., and Scheper, W. (2012). Rab6 is a modulator of the unfolded protein response: implications for Alzheimer’s disease. J. Alzheimers Dis. 28, 917–929.
Fagioli, C., and Sitia, R. (2001). Glycoprotein quality control in the endoplasmic reticulum. Mannose trimming by endoplasmic reticulum mannosidase I times the proteasomal degradation of unassembled immunoglobulin subunits. J. Biol. Chem. 276, 12885–12892.
Haberman, A., Williamson, W.R., Epstein, D., Wang, D., Rina, S., Meinertzhagen, I.A., and Hiesinger, P.R. (2012). The synaptic vesicle SNARE neuronal Synaptobrevin promotes endolysosomal degradation and prevents neurodegeneration. J. Cell Biol. 196, 261–276.
Harding, H.P., Zhang, Y., Zeng, H., Novoa, I., Lu, P.D., Calfon, M., Sadri, N., Yun, C., Popko, B., Paules, R., et al. (2003). An integrated stress response regulates amino acid metabolism and resis-tance to oxidative stress. Mol. Cell 11, 619–633.
Hebert, D.N., Garman, S.C., and Molinari, M. (2005). The glycan code of the endoplasmic reticulum: asparagine-linked carbohydrates as protein maturation and quality-control tags. Trends Cell Biol. 15, 364–370.
Hetz, C., Thielen, P., Matus, S., Nassif, M., Court, F., Kiffin, R., Martinez, G., Cuervo, A.M., Brown, R.H., and Glimcher, L.H. (2009). XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev. 23, 2294–2306.
Hoozemans, J.J., Veerhuis, R., Rozemuller, A.J., Baas, F., Eikelenboom, P., and Scheper, W. (2005). The unfolded protein response is activated in Alzheimer’s disease. Acta Neuropathol. (Berl) 110, 165–172.
Hoozemans, J.J.M., Van Haastert, E.S., Nijholt, D.A.T., Rozemuller, A.J.M., Eikelenboom, P., and Scheper, W. (2009). The Unfolded Protein Response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am. J. Pathol. 174, 1241–1251.
Hosokawa, N., Tremblay, L.O., You, Z., Herscovics, A., Wada, I., and Nagata, K. (2003). Enhancement of endoplasmic reticulum (ER) degradation of misfolded Null Hong Kong alpha1-antitrypsin by human ER mannosidase I. J. Biol. Chem. 278, 26287–26294.
Hosokawa, N., Hara, Y., and Mizushima, N. (2006). Generation of cell lines with tetracycline-regulated autophagy and a role for autophagy in controlling cell size. FEBS Lett. 580, 2623–2629.
Kanuka, H., Kuranaga, E., Hiratou, T., Igaki, T., Nelson, B., Okano, H., and Miura, M. (2003). Cytosol-endoplasmic reticulum interplay by Sec61alpha translocon in polyglutamine-mediated neurotoxicity in Drosophila. Proc. Natl. Acad. Sci. USA 100, 11723–11728.
Kanuka, H., Hiratou, T., Igaki, T., Kanda, H., Kuranaga, E., Sawamoto, K., Aigaki, T., Okano, H., and Miura, M. (2005). Gain-offunction screen identifies a role of the Sec61alpha translocon in Drosophila postmitotic neurotoxicity. Biochim. Biophys. Acta 1726, 225–237.
Korolchuk, V.I., Saiki, S., Lichtenberg, M., Siddiqi, F.H., Roberts, E.A., Imarisio, S., Jahreiss, L., Sarkar, S., Futter, M., Menzies, F.M., et al. (2011). Lysosomal positioning coordinates cellular nutrient responses. Nat. Cell Biol. 13, 453–460.
Miura, H., Hashida, K., Sudo, H., Awa, Y., Takarada-Iemata, M., Kokame, K., Takahashi, T., Matsumoto, M., Kitao, Y., and Hori, O. (2010). Deletion of Herp facilitates degradation of cytosolic proteins. Genes Cells 15, 843–853.
Molinari, M., Calanca, V., Galli, C., Lucca, P., and Paganetti, P. (2003). Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle. Science 299, 1397–1400.
Nakatsukasa, K., and Brodsky, J.L. (2008). The recognition and retrotranslocation of misfolded proteins from the endoplasmic reticulum. Traffic 9, 861–870.
Nijholt, D.A., de Graaf, T.R., Van Haastert, E.S., Oliveira, A.O., Berkers, C.R., Zwart, R., Ovaa, H., Baas, F., Hoozemans, J.J., and Scheper, W. (2011a). Endoplasmic reticulum stress activates autophagy but not the proteasome in neuronal cells: implications for Alzheimer’s disease. Cell Death Differ. 18, 1071–1081.
Nijholt, D.A., De, K.L., Elfrink, H.L., Hoozemans, J.J., and Scheper, W. (2011b). Removing protein aggregates: the role of proteolysis in neurodegeneration. Curr. Med. Chem. 18, 2459–2476.
Nijholt, D.A., Van Haastert, E.S., Rozemuller, A.J., Scheper, W., and Hoozemans, J.J. (2012). The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies. J. Pathol. 226, 693–702.
Nixon, R.A., and Yang, D.S. (2011). Autophagy failure in Alzheimer’s disease-locating the primary defect. Neurobiol. Dis. 43, 38–45.
Ogata, M., Hino, S., Saito, A., Morikawa, K., Kondo, S., Kanemoto, S., Murakami, T., Taniguchi, M., Tanii, I., Yoshinaga, K., et al. (2006). Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell. Biol. 26, 9220–9231.
Rafiq, M.A., Kuss, A.W., Puettmann, L., Noor, A., Ramiah, A., Ali, G., Hu, H., Kerio, N.A., Xiang, Y., Garshasbi, M., et al. (2011). Mutations in the alpha 1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability. Am. J. Hum. Genet. 89, 176–182.
Ron, D., and Walter, P. (2007). Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529.
Ron, E., Shenkman, M., Groisman, B., Izenshtein, Y., Leitman, J., and Lederkremer, G.Z. (2011). Bypass of glycan-dependent glycoprotein delivery to ERAD by up-regulated EDEM1. Mol. Biol. Cell 22, 3945–3954.
Scheper, W., and Hoozemans, J.J. (2009). Endoplasmic reticulum protein quality control in neurodegenerative disease: the good, the bad and the therapy. Curr. Med. Chem. 16, 615–626.
Scheper, W., Nijholt, D.A., and Hoozemans, J.J. (2011). The unfolded protein response and proteostasis in Alzheimer disease: preferential activation of autophagy by endoplasmic reticulum stress. Autophagy 7, 910–911.
Szegezdi, E., Logue, S.E., Gorman, A.M., and Samali, A. (2006). Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 7, 880–885.
Tyler, R.E., Pearce, M.M., Shaler, T.A., Olzmann, J.A., Greenblatt, E.J., and Kopito, R.R. (2012). Unassembled CD147 is an endogenous endoplasmic reticulum-associated degradation substrate. Mol. Biol. Cell 23, 4668–4678.
Vembar, S.S., and Brodsky, J.L. (2008). One step at a time: endoplasmic reticulum-associated degradation. Nat. Rev. Mol. Cell Biol. 9, 944–957.
Wang, F., Song, W., Brancati, G., and Segatori, L. (2011). Inhibition of endoplasmic reticulum-associated degradation rescues native folding in loss of function protein misfolding diseases. J. Biol. Chem. 286, 43454–43464.
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Elfrink, H.L., Zwart, R., Baas, F. et al. Inhibition of endoplasmic reticulum associated degradation reduces endoplasmic reticulum stress and alters lysosomal morphology and distribution. Mol Cells 35, 291–297 (2013). https://doi.org/10.1007/s10059-013-2286-9
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DOI: https://doi.org/10.1007/s10059-013-2286-9