{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T05:03:28Z","timestamp":1779339808887,"version":"3.51.4"},"reference-count":66,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T00:00:00Z","timestamp":1621382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Council for Scientific Research and Development","award":["422867\/2016-0"],"award-info":[{"award-number":["422867\/2016-0"]}]},{"name":"Council for Scientific Research and Development","award":["307832\/2015-5"],"award-info":[{"award-number":["307832\/2015-5"]}]},{"name":"Medical Research Council","award":["MR\/K019384\/1"],"award-info":[{"award-number":["MR\/K019384\/1"]}]},{"name":"Brazilian Federal Agency for Support and Evaluation of Graduate Education \u2013 CAPES","award":["Finance Code 001"],"award-info":[{"award-number":["Finance Code 001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>The heat shock protein 90 (Hsp90) is thought to be an excellent drug target against parasitic diseases. The leishmanicidal effect of an Hsp90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), was previously demonstrated in both in vitro and in vivo models of cutaneous leishmaniasis. Parasite death was shown to occur in association with severe ultrastructural alterations in Leishmania, suggestive of autophagic activation. We hypothesized that 17-AAG treatment results in the abnormal activation of the autophagic pathway, leading to parasite death. To elucidate this process, experiments were performed using transgenic parasites with GFP-ATG8-labelled autophagosomes. Mutant parasites treated with 17-AAG exhibited autophagosomes that did not entrap cargo, such as glycosomes, or fuse with lysosomes. ATG5-knockout (\u0394atg5) parasites, which are incapable of forming autophagosomes, demonstrated lower sensitivity to 17-AAG-induced cell death when compared to wild-type (WT) Leishmania, further supporting the role of autophagy in 17-AAG-induced cell death. In addition, Hsp90 inhibition resulted in greater accumulation of ubiquitylated proteins in both WT- and \u0394atg5-treated parasites compared to controls, in the absence of proteasome overload. In conjunction with previously described ultrastructural alterations, herein we present evidence that treatment with 17-AAG causes abnormal activation of the autophagic pathway, resulting in the formation of immature autophagosomes and, consequently, incidental parasite death.<\/jats:p>","DOI":"10.3390\/microorganisms9051089","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T21:49:21Z","timestamp":1621460961000},"page":"1089","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["17-AAG-Induced Activation of the Autophagic Pathway in Leishmania Is Associated with Parasite Death"],"prefix":"10.3390","volume":"9","author":[{"given":"Antonio Luis de O. A.","family":"Petersen","sequence":"first","affiliation":[{"name":"Laboratory of Parasite-Host Interaction and Epidemiology (LAIPHE), Gon\u00e7alo Moniz Institute\u2014FIOCRUZ, Salvador 40296-710, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6814-5669","authenticated-orcid":false,"given":"Benjamin","family":"Cull","sequence":"additional","affiliation":[{"name":"Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7433-3869","authenticated-orcid":false,"given":"Beatriz R. S.","family":"Dias","sequence":"additional","affiliation":[{"name":"Laboratory of Parasite-Host Interaction and Epidemiology (LAIPHE), Gon\u00e7alo Moniz Institute\u2014FIOCRUZ, Salvador 40296-710, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luana C.","family":"Palma","sequence":"additional","affiliation":[{"name":"Laboratory of Parasite-Host Interaction and Epidemiology (LAIPHE), Gon\u00e7alo Moniz Institute\u2014FIOCRUZ, Salvador 40296-710, Brazil"},{"name":"Post-Graduate Program in Experimental Pathology, Federal University of Bahia (UFBA), Salvador 40110-909, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasmin da S.","family":"Luz","sequence":"additional","affiliation":[{"name":"Laboratory of Parasite-Host Interaction and Epidemiology (LAIPHE), Gon\u00e7alo Moniz Institute\u2014FIOCRUZ, Salvador 40296-710, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9380-8839","authenticated-orcid":false,"given":"Juliana P. B.","family":"de Menezes","sequence":"additional","affiliation":[{"name":"Laboratory of Parasite-Host Interaction and Epidemiology (LAIPHE), Gon\u00e7alo Moniz Institute\u2014FIOCRUZ, Salvador 40296-710, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5574-3766","authenticated-orcid":false,"given":"Jeremy C.","family":"Mottram","sequence":"additional","affiliation":[{"name":"Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK"},{"name":"Department of Biology, York Biomedical Research Institute, University of York, York YO10 5DD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8308-9263","authenticated-orcid":false,"given":"Patr\u00edcia S. T.","family":"Veras","sequence":"additional","affiliation":[{"name":"Laboratory of Parasite-Host Interaction and Epidemiology (LAIPHE), Gon\u00e7alo Moniz Institute\u2014FIOCRUZ, Salvador 40296-710, Brazil"},{"name":"National Institute of Tropical Disease (INCT-DT), National Council for Scientific and Technological Development (CNPq), Bras\u00edlia 71605-001, DF, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/S0140-6736(98)10178-2","article-title":"Leishmaniasis","volume":"354","author":"Herwaldt","year":"1999","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-308X(06)64001-3","article-title":"Leishmania and the leishmaniases: A parasite genetic update and advances in taxonomy, epidemiology and pathogenicity in humans","volume":"64","author":"Banuls","year":"2007","journal-title":"Adv. Parasitol."},{"key":"ref_3","unstructured":"World Health Organization (2010). Control of the Leishmaniases. World Health Organ. Tech. Rep. Ser., Xii\u2013Xiii, 1\u2013186."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.actatropica.2011.02.007","article-title":"Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the new world","volume":"118","author":"Oliveira","year":"2011","journal-title":"Acta Trop."},{"key":"ref_5","first-page":"399","article-title":"Current scenario of drug development for leishmaniasis","volume":"123","author":"Croft","year":"2006","journal-title":"Indian J. Med. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1128\/CMR.19.1.111-126.2006","article-title":"Drug resistance in leishmaniasis","volume":"19","author":"Croft","year":"2006","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_7","first-page":"815023","article-title":"Advances in development of new treatment for leishmaniasis","volume":"2015","author":"Guedes","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2","DOI":"10.2174\/1872208311307010002","article-title":"A review of recent patents on the protozoan parasite hsp90 as a drug target","volume":"7","author":"Angel","year":"2013","journal-title":"Recent Pat. Biotechnol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.bbamcr.2011.12.003","article-title":"Heat shock protein 90 from neglected protozoan parasites","volume":"1823","author":"Roy","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"143","DOI":"10.2174\/092986611794475002","article-title":"Intracellular protozoan parasites of humans: The role of molecular chaperones in development and pathogenesis","volume":"18","author":"Shonhai","year":"2011","journal-title":"Protein Pept. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3307","DOI":"10.1091\/mbc.12.11.3307","article-title":"Heat shock protein 90 homeostasis controls stage differentiation in leishmania donovani","volume":"12","author":"Wiesgigl","year":"2001","journal-title":"Mol. Biol. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.bbrc.2003.10.045","article-title":"Molecular cloning of the 82-kda heat shock protein (hsp90) of toxoplasma gondii associated with the entry into and growth in host cells","volume":"311","author":"Ahn","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"37964","DOI":"10.1074\/jbc.M110.155317","article-title":"Heat shock protein 90 as a drug target against protozoan infections: Biochemical characterization of hsp90 from plasmodium falciparum and trypanosoma evansi and evaluation of its inhibitor as a candidate drug","volume":"285","author":"Pallavi","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1093\/infdis\/jit179","article-title":"Potent antitrypanosomal activities of heat shock protein 90 inhibitors in vitro and in vivo","volume":"208","author":"Meyer","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Petersen, A.L., Guedes, C.E., Versoza, C.L., Lima, J.G., de Freitas, L.A., Borges, V.M., and Veras, P.S. (2012). 17-aag kills intracellular leishmania amazonensis while reducing inflammatory responses in infected macrophages. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049496"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Santos, D.M., Petersen, A.L., Celes, F.S., Borges, V.M., Veras, P.S., and de Oliveira, C.I. (2014). Chemotherapeutic potential of 17-aag against cutaneous leishmaniasis caused by leishmania (viannia) braziliensis. PLoS Negl. Trop. Dis., 8.","DOI":"10.1371\/journal.pntd.0003275"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1093\/hmg\/ddn419","article-title":"17-dmag ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an sbma model mouse","volume":"18","author":"Tokui","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1158\/1078-0432.CCR-11-1000","article-title":"Hsp90 molecular chaperone inhibitors: Are we there yet?","volume":"18","author":"Neckers","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S1535-6108(03)00029-1","article-title":"Heat shock protein 90 as a molecular target for cancer therapeutics","volume":"3","author":"Isaacs","year":"2003","journal-title":"Cancer Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/bip.21292","article-title":"Hsp90 and co-chaperones twist the functions of diverse client proteins","volume":"93","author":"Zuehlke","year":"2010","journal-title":"Biopolymers"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.canlet.2012.06.016","article-title":"Molecular crosstalk between the proteasome, aggresomes and autophagy: Translational potential and clinical implications","volume":"325","author":"Driscoll","year":"2012","journal-title":"Cancer Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.cell.2014.03.007","article-title":"Differential scales of protein quality control","volume":"157","author":"Wolff","year":"2014","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/nrm2993","article-title":"Cellular strategies for controlling protein aggregation","volume":"11","author":"Tyedmers","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1093\/hmg\/10.12.1307","article-title":"Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of huntington\u2019s disease","volume":"10","author":"Sittler","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","article-title":"Autophagy: Renovation of cells and tissues","volume":"147","author":"Mizushima","year":"2011","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1124\/pr.112.007120","article-title":"Therapeutic targeting of autophagy in disease: Biology and pharmacology","volume":"65","author":"Cheng","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1126\/science.290.5497.1717","article-title":"Autophagy as a regulated pathway of cellular degradation","volume":"290","author":"Klionsky","year":"2000","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.tcb.2007.04.005","article-title":"Eating the endoplasmic reticulum: Quality control by autophagy","volume":"17","author":"Yorimitsu","year":"2007","journal-title":"Trends Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1146\/annurev.nutr.27.061406.093749","article-title":"Protein turnover via autophagy: Implications for metabolism","volume":"27","author":"Mizushima","year":"2007","journal-title":"Annu. Rev. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"445","DOI":"10.4161\/auto.19496","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy","volume":"8","author":"Klionsky","year":"2012","journal-title":"Autophagy"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"127","DOI":"10.4161\/auto.7.2.13310","article-title":"Autophagy in protists","volume":"7","author":"Duszenko","year":"2011","journal-title":"Autophagy"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"106","DOI":"10.4161\/auto.3595","article-title":"Atg genes involved in non-selective autophagy are conserved from yeast to man, but the selective cvt and pexophagy pathways also require organism-specific genes","volume":"3","author":"Meijer","year":"2007","journal-title":"Autophagy"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11384","DOI":"10.1074\/jbc.M512307200","article-title":"Endosome sorting and autophagy are essential for differentiation and virulence of leishmania major","volume":"281","author":"Besteiro","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.ijpara.2007.03.008","article-title":"Protein turnover and differentiation in leishmania","volume":"37","author":"Besteiro","year":"2007","journal-title":"Int. J. Parasitol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Williams, R.A., Smith, T.K., Cull, B., Mottram, J.C., and Coombs, G.H. (2012). Atg5 is essential for atg8-dependent autophagy and mitochondrial homeostasis in leishmania major. PLoS Pathog, 8.","DOI":"10.1371\/journal.ppat.1002695"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1016\/j.biocel.2004.02.002","article-title":"Regulation and role of autophagy in mammalian cells","volume":"36","author":"Meijer","year":"2004","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S1534-5807(04)00099-1","article-title":"Development by self-digestion: Molecular mechanisms and biological functions of autophagy","volume":"6","author":"Levine","year":"2004","journal-title":"Dev. Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1172\/JCI26390","article-title":"Autophagy in cell death: An innocent convict?","volume":"115","author":"Levine","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"187850","DOI":"10.4061\/2011\/187850","article-title":"Cryptolepine-induced cell death of leishmania donovani promastigotes is augmented by inhibition of autophagy","volume":"2011","author":"Sengupta","year":"2011","journal-title":"Mol. Biol. Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.4161\/auto.36438","article-title":"Glycosome turnover in leishmania major is mediated by autophagy","volume":"10","author":"Cull","year":"2014","journal-title":"Autophagy"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"16249","DOI":"10.1074\/jbc.274.23.16249","article-title":"Protease trafficking in two primitive eukaryotes is mediated by a prodomain protein motif","volume":"274","author":"Engel","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"159","DOI":"10.4161\/auto.5.2.7328","article-title":"Characterization of unusual families of atg8-like proteins and atg12 in the protozoan parasite leishmania major","volume":"5","author":"Williams","year":"2009","journal-title":"Autophagy"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1111\/j.1365-2818.2006.01706.x","article-title":"A guided tour into subcellular colocalization analysis in light microscopy","volume":"224","author":"Bolte","year":"2006","journal-title":"J. Microsc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.cell.2004.05.002","article-title":"Two enzymes in one; two yeast peroxiredoxins display oxidative stress-dependent switching from a peroxidase to a molecular chaperone function","volume":"117","author":"Jang","year":"2004","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7271","DOI":"10.1158\/1078-0432.CCR-07-1595","article-title":"The roles of therapy-induced autophagy and necrosis in cancer treatment","volume":"13","author":"Amaravadi","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/auto.26743","article-title":"The multifunctional autophagy pathway in the human malaria parasite, plasmodium falciparum","volume":"10","author":"Cervantes","year":"2014","journal-title":"Autophagy"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2370","DOI":"10.1128\/AAC.48.7.2370-2378.2004","article-title":"Antimalarial quinolines and artemisinin inhibit endocytosis in plasmodium falciparum","volume":"48","author":"Hoppe","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/nrm2938","article-title":"Heat shock factors: Integrators of cell stress, development and lifespan","volume":"11","author":"Akerfelt","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/381571a0","article-title":"Molecular chaperones in cellular protein folding","volume":"381","author":"Hartl","year":"1996","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/nature10317","article-title":"Molecular chaperones in protein folding and proteostasis","volume":"475","author":"Hartl","year":"2011","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3494","DOI":"10.1091\/mbc.e05-12-1096","article-title":"The hsp90 chaperone complex regulates gdi-dependent rab recycling","volume":"17","author":"Chen","year":"2006","journal-title":"Mol. Biol. Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1242\/jcs.015610","article-title":"A novel hsp90 chaperone complex regulates intracellular vesicle transport","volume":"121","author":"Lotz","year":"2008","journal-title":"J. Cell Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"17096","DOI":"10.1038\/nmicrobiol.2017.96","article-title":"Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection","volume":"2","author":"Dou","year":"2017","journal-title":"Nat. Microbiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1056\/NEJMra1205406","article-title":"Autophagy in human health and disease","volume":"368","author":"Choi","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ccr.2006.06.001","article-title":"Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis","volume":"10","author":"Degenhardt","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.cell.2004.11.046","article-title":"Growth factor regulation of autophagy and cell survival in the absence of apoptosis","volume":"120","author":"Lum","year":"2005","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Nguyen, H.M., Berry, L., Sullivan, W.J., and Besteiro, S. (2017). Autophagy participates in the unfolded protein response in toxoplasma gondii. FEMS Microbiol. Lett., 364.","DOI":"10.1093\/femsle\/fnx153"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1038\/nature06639","article-title":"Autophagy fights disease through cellular self-digestion","volume":"451","author":"Mizushima","year":"2008","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1038\/s41419-018-1229-y","article-title":"Dysregulated autophagy contributes to caspase-dependent neuronal apoptosis","volume":"9","author":"Chung","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1111\/j.1365-2958.2006.05274.x","article-title":"Cysteine peptidases cpa and cpb are vital for autophagy and differentiation in leishmania mexicana","volume":"61","author":"Williams","year":"2006","journal-title":"Mol. Microbiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.bbamcr.2011.08.006","article-title":"Quality control and fate determination of hsp90 client proteins","volume":"1823","author":"Theodoraki","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1002\/glia.21047","article-title":"Autophagy is activated by proteasomal inhibition and involved in aggresome clearance in cultured astrocytes","volume":"58","author":"Janen","year":"2010","journal-title":"Glia"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5404","DOI":"10.1074\/jbc.TM117.000117","article-title":"Ubiquitin signaling and autophagy","volume":"293","author":"Grumati","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Grumati, P., Morozzi, G., Holper, S., Mari, M., Harwardt, M.I., Yan, R., Muller, S., Reggiori, F., Heilemann, M., and Dikic, I. (2017). Full length rtn3 regulates turnover of tubular endoplasmic reticulum via selective autophagy. Elife, 6.","DOI":"10.7554\/eLife.25555"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s13311-013-0255-9","article-title":"Chronic treatment with 17-dmag improves balance and coordination in a new mouse model of machado-joseph disease","volume":"11","author":"Amorim","year":"2014","journal-title":"Neurotherapeutics"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.arr.2016.09.004","article-title":"Targeting chaperones, heat shock factor-1, and unfolded protein response: Promising therapeutic approaches for neurodegenerative disorders","volume":"35","author":"Bose","year":"2017","journal-title":"Ageing Res. Rev."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/9\/5\/1089\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:03:49Z","timestamp":1760162629000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/9\/5\/1089"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,19]]},"references-count":66,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["microorganisms9051089"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms9051089","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,19]]}}}