GRASP55 regulates the unconventional secretion and aggregation of mutant huntingtin

Abstract

Recent studies demonstrated that the Golgi reassembly stacking proteins (GRASPs), especially GRASP55, regulate Golgi-independent unconventional secretion of certain cytosolic and transmembrane cargoes; however, the underlying mechanism remains unknown. Here, we surveyed several neurodegenerative disease–related proteins, including mutant huntingtin (Htt-Q74), superoxide dismutase 1 (SOD1), tau, and TAR DNA–binding protein 43 (TDP-43), for unconventional secretion; our results show that Htt-Q74 is most robustly secreted in a GRASP55-dependent manner. Using Htt-Q74 as a model system, we demonstrate that unconventional secretion of Htt is GRASP55 and autophagy dependent and is enhanced under stress conditions such as starvation and endoplasmic reticulum stress. Mechanistically, we show that GRASP55 facilitates Htt secretion by tethering autophagosomes to lysosomes to promote autophagosome maturation and subsequent lysosome secretion and by stabilizing p23/TMED10, a channel for translocation of cytoplasmic proteins into the lumen of the endoplasmic reticulum–Golgi intermediate compartment. Moreover, we found that GRASP55 levels are upregulated by various stresses to facilitate unconventional secretion, whereas inhibition of Htt-Q74 secretion by GRASP55 KO enhances Htt aggregation and toxicity. Finally, comprehensive secretomic analysis identified novel cytosolic cargoes secreted by the same unconventional pathway, including transgelin (TAGLN), multifunctional protein ADE2 (PAICS), and peroxiredoxin-1 (PRDX1). In conclusion, this study defines the pathway of GRASP55-mediated unconventional protein secretion and provides important insights into the progression of Huntington’s disease. Recent studies demonstrated that the Golgi reassembly stacking proteins (GRASPs), especially GRASP55, regulate Golgi-independent unconventional secretion of certain cytosolic and transmembrane cargoes; however, the underlying mechanism remains unknown. Here, we surveyed several neurodegenerative disease–related proteins, including mutant huntingtin (Htt-Q74), superoxide dismutase 1 (SOD1), tau, and TAR DNA–binding protein 43 (TDP-43), for unconventional secretion; our results show that Htt-Q74 is most robustly secreted in a GRASP55-dependent manner. Using Htt-Q74 as a model system, we demonstrate that unconventional secretion of Htt is GRASP55 and autophagy dependent and is enhanced under stress conditions such as starvation and endoplasmic reticulum stress. Mechanistically, we show that GRASP55 facilitates Htt secretion by tethering autophagosomes to lysosomes to promote autophagosome maturation and subsequent lysosome secretion and by stabilizing p23/TMED10, a channel for translocation of cytoplasmic proteins into the lumen of the endoplasmic reticulum–Golgi intermediate compartment. Moreover, we found that GRASP55 levels are upregulated by various stresses to facilitate unconventional secretion, whereas inhibition of Htt-Q74 secretion by GRASP55 KO enhances Htt aggregation and toxicity. Finally, comprehensive secretomic analysis identified novel cytosolic cargoes secreted by the same unconventional pathway, including transgelin (TAGLN), multifunctional protein ADE2 (PAICS), and peroxiredoxin-1 (PRDX1). In conclusion, this study defines the pathway of GRASP55-mediated unconventional protein secretion and provides important insights into the progression of Huntington’s disease. Neurodegenerative diseases are characterized by increased neuronal cell death and decreased cognitive abilities of patients. Different diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease (HD), and amyotrophic lateral sclerosis, are caused by different protein-based aberrations that affect different pathways; yet all cause neuronal cell death by forming inclusion bodies (1Lee H.J. Patel S. Lee S.J. Intravesicular localization and exocytosis of alpha-synuclein and its aggregates.J. Neurosci. 2005; 25: 6016-6024Crossref PubMed Scopus (618) Google Scholar, 2Umeda T. Maekawa S. Kimura T. Takashima A. Tomiyama T. Mori H. Neurofibrillary tangle formation by introducing wild-type human tau into APP transgenic mice.Acta Neuropathol. 2014; 127: 685-698Crossref PubMed Scopus (43) Google Scholar, 3Arrasate M. Finkbeiner S. Protein aggregates in Huntington's disease.Exp. Neurol. 2012; 238: 1-11Crossref PubMed Scopus (237) Google Scholar). These include protein aggregates formed by hyperphosphorylated tau in Alzheimer’s disease (2Umeda T. Maekawa S. Kimura T. Takashima A. Tomiyama T. Mori H. Neurofibrillary tangle formation by introducing wild-type human tau into APP transgenic mice.Acta Neuropathol. 2014; 127: 685-698Crossref PubMed Scopus (43) Google Scholar), mutant superoxide dismutase 1 (SOD1) (4Dangoumau A. Verschueren A. Hammouche E. Papon M.A. Blasco H. Cherpi-Antar C. et al.Novel SOD1 mutation p.V31A identified with a slowly progressive form of amyotrophic lateral sclerosis.Neurobiol. Aging. 2014; 35: 266.e1-e4Crossref Scopus (13) Google Scholar), and TAR DNA–binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (5Johnson B.S. Snead D. Lee J.J. McCaffery J.M. Shorter J. Gitler A.D. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity.J. Biol. Chem. 2009; 284: 20329-20339Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar), and mutant huntingtin (Htt) in HD (6Bates G.P. Dorsey R. Gusella J.F. Hayden M.R. Kay C. Leavitt B.R. et al.Huntington disease.Nat. Rev. Dis. Primers. 2015; 115005Crossref PubMed Scopus (747) Google Scholar, 7Saudou F. Humbert S. The Biology of huntingtin.Neuron. 2016; 89: 910-926Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar). Many of these neurotoxic proteins have been detected in the cerebrospinal fluid (CSF) of patients with diseases, indicating that these proteins could be secreted from cells (8Wild E.J. Boggio R. Langbehn D. Robertson N. Haider S. Miller J.R. et al.Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients.J. Clin. Invest. 2015; 125: 1979-1986Crossref PubMed Scopus (144) Google Scholar, 9Mecocci P. Cherubini A. Bregnocchi M. Chionne F. Cecchetti R. Lowenthal D.T. et al.Tau protein in cerebrospinal fluid: a and in Dis. PubMed Google Scholar, D. S. D. M. A. et in fluid as a for Neurol. PubMed Scopus Google Scholar). the secretion protein aggregation and in and secretion facilitates the of proteins to In the pathway, transmembrane and proteins, such as the are in the endoplasmic reticulum and to the from are to neurotoxic proteins, such as tau, and are as cytosolic of these proteins is of the pathway in the Golgi as a mutant Htt in form in and form in (8Wild E.J. Boggio R. Langbehn D. Robertson N. Haider S. Miller J.R. et al.Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients.J. Clin. Invest. 2015; 125: 1979-1986Crossref PubMed Scopus (144) Google a unconventional pathway H. D. huntingtin is secreted a unconventional Neurosci. PubMed Scopus Google Scholar, R. C. et huntingtin is from the in Neurosci. PubMed Scopus Google Scholar). is the that unconventional secretion, and the and Golgi-independent unconventional secretion been the unconventional pathway is of the unconventional secretion of cytosolic proteins the Golgi reassembly stacking protein of GRASP55 S. secretion of proteins to in Biol. 2016; PubMed Google Scholar, C. A.D. a Biol. 2016; PubMed Google Scholar, J. S. M. P. J. et secretion of by and Biol. PubMed Scopus Google Scholar). GRASP55, and its characterized as Golgi stacking proteins M. J. a protein in the stacking of Golgi Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. Shorter J. for as a Golgi stacking J. PubMed Scopus Google Scholar). form to the Golgi into the GRASP55 and and in Golgi Biol. PubMed Scopus Google Scholar). of GRASP55 and by KO of by results in Golgi GRASP55 and and in Golgi Biol. PubMed Scopus Google Scholar, J. H. D. et of the Golgi stacking proteins GRASP55 and Golgi and Biol. PubMed Google Scholar). to unconventional secretion of protein in and J.M. C. C. secretion of is by Biol. PubMed Scopus Google Scholar, M.A. C. D. The protein is for unconventional protein secretion Full Text Full Text PDF PubMed Scopus Google Scholar). In the protein is in unconventional of of H. C. secretion is for Full Text Full Text PDF PubMed Scopus Google Scholar). In are for unconventional of transmembrane and the Lee of a unconventional secretion Full Text Full Text PDF PubMed Scopus Google Scholar, N. S. M. D. unconventional pathway for of J. PubMed Scopus Google Scholar). GRASP55 unconventional secretion and GRASP55 is for secretion of neurotoxic proteins such as Htt are unknown. In this we that mutant Htt is secreted in a GRASP55-dependent manner. Htt secretion is under stress including and inhibition of and of all of GRASP55 GRASP55 facilitates Htt secretion is to accelerate by autophagosome and lysosome the is to p23/TMED10, a protein channel in the intermediate that cytosolic proteins into the lumen for unconventional Finally, we and secretomic analysis of and GRASP55 KO cells and identified a of cytoplasmic proteins secretion GRASP55 is for the secretion of cytosolic proteins to we a of neurotoxic proteins, including Htt 1 with a SOD1 TDP-43 and tau in and cells we J. H. D. et of the Golgi stacking proteins GRASP55 and Golgi and Biol. PubMed Google Scholar). we the Htt 1 been that this is to and detected in the with in HD A. C. et of the 1 protein in S. A. PubMed Scopus Google Scholar, M. of 1 protein and the for the of Huntington's S. A. PubMed Scopus Google Scholar, Boggio R. M. C. et of mutant huntingtin in human cerebrospinal fluid by Dis. PubMed Scopus Google Scholar, N. S. Patel R. et disease PubMed Scopus Google Scholar). we the cells in a for and the of the in the by pathway as a these proteins found in the Htt-Q74 secretion the most and GRASP55 dependent we as a to study the mechanism of GRASP55-dependent unconventional GRASP55 and have been to be in unconventional secretion J. H. et and of is a for unconventional secretion of 2016; PubMed Google Scholar), we in KO GRASP55 and to cells Htt in the as by the to of cells Htt aggregates that as in the these Htt aggregates found in the the Golgi to the of Htt Golgi Htt to affect Golgi Htt aggregates Golgi as Golgi stress to in Huntington's S. A. PubMed Scopus Google Scholar, H. F. is for and for the 2014; PubMed Scopus Google Scholar), and the in cells we in form aggregates affect the Golgi of tau in cells the Golgi we Htt secretion is of in and KO cells for we the cells in for and the of Htt in the by Htt in the and the in cells and indicating that Htt secretion GRASP55 and of a secreted by the pathway, by KO In this and cytosolic proteins, and detected in the and In cause cell death as by the These results that Htt secreted from Golgi especially in whereas that Htt is secreted unconventional Golgi-independent pathway, we by in and in the indicating a of Htt secretion by that is secreted a Golgi-independent unconventional The of Htt is with the of the the 1 Htt with in the is as a disease mutant (6Bates G.P. Dorsey R. Gusella J.F. Hayden M.R. Kay C. Leavitt B.R. et al.Huntington disease.Nat. Rev. Dis. Primers. 2015; 115005Crossref PubMed Scopus (747) Google Scholar, 7Saudou F. Humbert S. The Biology of huntingtin.Neuron. 2016; 89: 910-926Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar). the of the Htt secretion, we and in the same cells and in and and the of in the that of that the for secretion the the of Htt in secreted a as and secretion robustly in cells and Htt and the detected in the we the the Htt is by such as and N. T. E. E. M. et mutant huntingtin toxicity.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and by 1 been to Htt aggregation and N. A. et and for by the and Biol. 2009; PubMed Scopus Google Scholar, A. P. N. et mutant and its aggregation and in Huntington's disease J. PubMed Scopus Google Scholar). the different of we cells with a a increased the of the whereas the that the a whereas the is a for Htt A. P. N. et mutant and its aggregation and in Huntington's disease J. PubMed Scopus Google Scholar), the and increased Htt secretion, whereas its secretion and indicating that the form of Htt is secreted with the form of these results demonstrate that unconventional secretion is to a certain and as a mechanism for cells to been demonstrated that unconventional secretion is under different stress conditions the autophagy is F. A. C. a stress Biol. PubMed Scopus Google Scholar), and that unconventional secretion of and autophagy autophagy H. J. et autophagy and in the unconventional secretion of PubMed Scopus Google Scholar, C. McCaffery J.M. J.M. of a novel for unconventional protein Biol. PubMed Scopus Google Scholar). In we that GRASP55 as to regulate autophagosome GRASP55 is and the GRASP55 is and from the Golgi to the autophagosomes and with autophagosomes and protein lysosomes and as a to facilitate J. E. GRASP55 to promote Full Text Full Text PDF PubMed Scopus Google Scholar). of GRASP55 under starvation of is by 1 J. E. 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