{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T22:53:48Z","timestamp":1779231228883,"version":"3.51.4"},"reference-count":54,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,1,18]],"date-time":"2019-01-18T00:00:00Z","timestamp":1547769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Human stefin B is a protease inhibitor from the family of cystatins. It was reported that it forms oligomers in cells. We have shown that it has a role in cell\u2019s response to misfolded proteins. We also have shown that its oligomers bind amyloid-beta (A\u03b2). Here, we discuss ways, how stefin B could reduce build-up of protein aggregates by other proteins and consequently reduces ROS and, how this might be connected to autophagy. When overexpressed, stefin B forms protein aggregates itself and these protein aggregates induce autophagy. Similarly, cystatin C was shown to bind A\u03b2 and to induce autophagy. It is also suggested how more knowledge about the role of stefin B in a cell\u2019s response to misfolded proteins could be used to modulate progressive myoclonus epilepsy of type 1 EPM1 disease.<\/jats:p>","DOI":"10.3390\/cells8010070","type":"journal-article","created":{"date-parts":[[2019,1,18]],"date-time":"2019-01-18T11:26:55Z","timestamp":1547810815000},"page":"70","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Possible Mechanisms by which Stefin B could Regulate Proteostasis and Oxidative Stress"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9793-8200","authenticated-orcid":false,"given":"Eva","family":"\u017derovnik","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular and Structural Biology, Jo\u017eef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1016\/j.biochi.2010.04.013","article-title":"Peptidase inhibitors in the MEROPS database","volume":"96","author":"Rawlings","year":"2010","journal-title":"Biochimie"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"79","DOI":"10.3389\/fnmol.2012.00079","article-title":"Cystatin C in Alzheimer\u2019s disease","volume":"5","author":"Kaur","year":"2012","journal-title":"Front. Mol. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"885","DOI":"10.3233\/JAD-2010-1291","article-title":"Cystatin C protects neuronal cells from amyloid-beta-induced toxicity","volume":"19","author":"Tizon","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Tizon, B., Sahoo, S., Yu, H., Gauthier, S., Kumar, A.R., Mohan, P., Figliola, M., Pawlik, M., Grubb, A., and Uchiyama, Y. (2010). Induction of autophagy by cystatin C: A mechanism that protects murine primary cortical neurons and neuronal cell lines. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009819"},{"key":"ref_5","first-page":"342","article-title":"Identification of mutations in cystatin B, the gene responsible for the Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1)","volume":"60","author":"Lalioti","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1126\/science.271.5256.1731","article-title":"Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1)","volume":"271","author":"Pennacchio","year":"1996","journal-title":"Science"},{"key":"ref_7","first-page":"146","article-title":"The expanded dodecamer repeat in Progressive myoclonus epilepsy (EPM1) is unstable, shows no correlation with age of onset, and results in reduced expression of reporter genes in vitro","volume":"6","author":"Lalioti","year":"1998","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1111\/j.1528-1167.2007.01422.x","article-title":"Molecular background of EPM1-Unverricht-Lundborg disease","volume":"49","author":"Joensuu","year":"2008","journal-title":"Epilepsia"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Polajnar, M., \u010ceru, S., Jerala, N.K., and \u017derovnik, E. (2012). Human stefin B normal and patho-physiological role: Molecular and cellular aspects of amyloid-type aggregation of certain EPM1 mutants. Front. Mol. Neurosci.","DOI":"10.3389\/fnmol.2012.00088"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1002\/prot.20812","article-title":"Folding and amyloid-fibril formation for a series of human stefins\u2019 chimeras: Any correlation?","volume":"62","author":"Kenig","year":"2006","journal-title":"Proteins"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1002\/prot.22156","article-title":"The mechanism of amyloid-fibril formation by stefin B: Temperature and protein concentration dependence of the rates","volume":"74","author":"Skerget","year":"2009","journal-title":"Proteins"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"18362","DOI":"10.3390\/ijms140918362","article-title":"The role of initial oligomers in amyloid fibril formation by human stefin B","volume":"14","author":"Kirsipuu","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3362","DOI":"10.1046\/j.1432-1033.2002.03024.x","article-title":"Amyloid-fibril formation. Proposed mechanisms and relevance to conformational disease","volume":"269","author":"Zerovnik","year":"2002","journal-title":"Eur. J. Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1515\/bchm3.1992.373.2.453","article-title":"Denaturation of stefin B by GuHCl, pH and heat; evidence for molten globule intermediates","volume":"373","author":"Zerovnik","year":"1992","journal-title":"Biol. Chem. Hoppe Seyler"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/(SICI)1097-0134(19980815)32:3<304::AID-PROT6>3.0.CO;2-H","article-title":"On the mechanism of human stefin B folding: II. Folding from GuHCl unfolded, TFE denatured, acid denatured, and acid intermediate states","volume":"32","author":"Zerovnik","year":"1998","journal-title":"Proteins"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1002\/(SICI)1097-0134(19990801)36:2<205::AID-PROT6>3.0.CO;2-4","article-title":"Differences in the effects of TFE on the folding pathways of human stefins A and B","volume":"36","author":"Zerovnik","year":"1999","journal-title":"Proteins"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ceru, S., Layfield, R., Zava\u0161nik-Bergant, T., Repnik, U., Kopitar-Jerala, N., Turk, V., and \u017derovnik, E. (2010). Intracellular aggregation of human stefin B; confocal and electron microscopy study. Biol Cell.","DOI":"10.1042\/BC20090163"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1016\/j.bbamcr.2014.05.018","article-title":"Gain in toxic function of stefin B EPM1 mutants aggregates: Correlation between cell death, aggregate number\/size and oxidative stress","volume":"1843","author":"Polajnar","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5910","DOI":"10.1523\/JNEUROSCI.0682-09.2009","article-title":"Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1","volume":"29","author":"Lehtinen","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Polajnar, M., Zavasnik-Bergant, T., Skerget, K., Vizovisek, M., Vidmar, R., Fonovic, M., Kopitar-Jerala, N., Petrovic, U., Navarro, S., and Ventura, S. (2014). Human stefin B role in cell\u2019s response to misfolded proteins and autophagy. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0102500"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.2353\/ajpath.2010.100461","article-title":"Cystatin C rescues degenerating neurons in a cystatin B-knockout mouse model of progressive myoclonus epilepsy","volume":"177","author":"Kaur","year":"2010","journal-title":"Am. J. Pathol"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/S0140-6736(83)90749-3","article-title":"\u201cBaltic\u201d myoclonus epilepsy: Hereditary disorder of childhood made worse by phenytoin","volume":"2","author":"Eldridge","year":"1983","journal-title":"Lancet"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1111\/j.1528-1167.2008.01546.x","article-title":"Clinical picture of EPM1-Unverricht-Lundborg disease","volume":"49","author":"Kalviainen","year":"2008","journal-title":"Epilepsia"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.1093\/hmg\/11.23.2941","article-title":"New insights into the molecular basis of progressive myoclonus epilepsy: A multiprotein complex with cystatin B","volume":"11","author":"Riccio","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3201","DOI":"10.1074\/jbc.M109.024620","article-title":"Interaction between oligomers of stefin B and amyloid-beta in vitro and in cells","volume":"285","author":"Bavdek","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1002\/bies.201000079","article-title":"Binding of amyloid peptides to domain-swapped dimers of other amyloid-forming proteins may prevent their neurotoxicity","volume":"32","author":"Zerovnik","year":"2010","journal-title":"Bioessays"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3042","DOI":"10.1111\/j.1742-4658.2005.04717.x","article-title":"Interaction of human stefin B in the prefibrillar oligomeric form with membranes. Correlation with cellular toxicity","volume":"272","author":"Anderluh","year":"2005","journal-title":"FEBS J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/3059","article-title":"Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice","volume":"20","author":"Pennacchio","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1111\/j.1528-1167.2006.00638.x","article-title":"Altered tryptophan metabolism in the brain of cystatin B-deficient mice: A model system for progressive myoclonus epilepsy","volume":"47","author":"Vaarmann","year":"2006","journal-title":"Epilepsia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1111\/j.1528-1167.2007.01118.x","article-title":"Substantial thalamostriatal dopaminergic defect in Unverricht-Lundborg disease","volume":"48","author":"Korja","year":"2007","journal-title":"Epilepsia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.nbd.2006.11.006","article-title":"A pathogenetic hypothesis of Unverricht-Lundborg disease onset and progression","volume":"25","author":"Franceschetti","year":"2007","journal-title":"Neurobiol. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1212\/WNL.0b013e3181b3888b","article-title":"Motor cortex and thalamic atrophy in Unverricht-Lundborg disease: Voxel-based morphometric study","volume":"73","author":"Koskenkorva","year":"2009","journal-title":"Neurology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.eplepsyres.2009.09.018","article-title":"T2-weighted high-intensity signals in the basal ganglia as an interesting image finding in Unverricht-Lundborg disease","volume":"88","author":"Korja","year":"2010","journal-title":"Epilepsy Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1080\/13506120802193555","article-title":"Size and morphology of toxic oligomers of amyloidogenic proteins: A case study of human stefin B","volume":"15","author":"Ceru","year":"2008","journal-title":"Amyloid"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.febslet.2007.12.002","article-title":"Similar toxicity of the oligomeric molten globule state and the prefibrillar oligomers","volume":"582","author":"Ceru","year":"2008","journal-title":"FEBS Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/978-1-60761-756-3_2","article-title":"Protein aggregation diseases: Toxicity of soluble prefibrillar aggregates and their clinical significance","volume":"648","author":"Stefani","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1111\/j.1742-4658.2008.06390.x","article-title":"Interaction with model membranes and pore formation by human stefin B: Studying the native and prefibrillar states","volume":"275","author":"Rabzelj","year":"2008","journal-title":"FEBS J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/sj.ejhg.5201300","article-title":"Loss of lysosomal association of cystatin B proteins representing progressive myoclonus epilepsy, EPM1, mutations","volume":"13","author":"Alakurtti","year":"2005","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.bbamcr.2007.08.007","article-title":"Cystatin B and its EPM1 mutants are polymeric and aggregate prone in vivo","volume":"1783","author":"Cipollini","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1110\/ps.051609705","article-title":"In vitro study of stability and amyloid-fibril formation of two mutants of human stefin B (cystatin B) occurring in patients with EPM1","volume":"14","author":"Rabzelj","year":"2005","journal-title":"Protein Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/S0962-8924(00)01852-3","article-title":"Aggresomes, inclusion bodies and protein aggregation","volume":"10","author":"Kopito","year":"2000","journal-title":"Trends Cell. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.bbadis.2008.10.002","article-title":"Autophagy and the ubiquitin-proteasome system: Collaborators in neuroprotection","volume":"1782","author":"Nedelsky","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.redox.2017.10.014","article-title":"Oxidative stress and the amyloid beta peptide in Alzheimer\u2019s disease","volume":"14","author":"Cheignon","year":"2018","journal-title":"Redox Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"12052","DOI":"10.1074\/jbc.M113.525212","article-title":"\u03b2-amyloid fibrils in Alzheimer disease are not inert when bound to copper ions but can degrade hydrogen peroxide and generate reactive oxygen species","volume":"289","author":"Mayes","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1006\/jsbi.2000.4274","article-title":"Review: Alzheimer\u2019s amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity","volume":"130","author":"Varadarajan","year":"2000","journal-title":"J. Struct. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4250","DOI":"10.1111\/j.1742-4658.2006.05426.x","article-title":"High affinity copper binding by stefin B (cystatin B) and its role in the inhibition of amyloid fibrillation","volume":"273","author":"Zerovnik","year":"2006","journal-title":"FEBS J."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Jena, K.K., Kolapalli, S.P., Mehto, S., Nath, P., Das, B., Sahoo, P.K., Ahad, A., Syed, G.H., Raghav, S.K., and Senapati, S. (2018). TRIM16 controls assembly and degradation of protein aggregates by modulating the p62-NRF2 axis and autophagy. EMBO J., 37.","DOI":"10.15252\/embj.201798358"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"E7043","DOI":"10.1073\/pnas.1803130115","article-title":"Hsp70-Bag3 complex is a hub for proteotoxicity-induced signaling that controls protein aggregation","volume":"115","author":"Meriin","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Zerovnik, E. (2016). Putative alternative functions of human stefin B (cystatin B): binding to amyloid-beta, membranes, and copper. J. Mol. Recognit.","DOI":"10.1002\/jmr.2562"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.molmed.2011.02.005","article-title":"Impaired autophagy: A link between neurodegenerative diseases and progressive myoclonus epilepsies","volume":"17","author":"Polajnar","year":"2011","journal-title":"Trends Mol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Polajnar, M., and Zerovnik, E. (2014). Impaired autophagy: A link between neurodegenerative and neuropsychiatric diseases. J. Cell. Mol. Med.","DOI":"10.1111\/jcmm.12349"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1093\/hmg\/ddi458","article-title":"Rapamycin alleviates toxicity of different aggregate-prone proteins","volume":"15","author":"Berger","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/ng1362","article-title":"Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease","volume":"36","author":"Ravikumar","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"620","DOI":"10.4161\/auto.4898","article-title":"Small molecule enhancers of rapamycin-induced TOR inhibition promote autophagy, reduce toxicity in Huntington\u2019s disease models and enhance killing of mycobacteria by macrophages","volume":"3","author":"Floto","year":"2007","journal-title":"Autophagy"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/1\/70\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:27:08Z","timestamp":1760185628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/1\/70"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,18]]},"references-count":54,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,1]]}},"alternative-id":["cells8010070"],"URL":"https:\/\/doi.org\/10.3390\/cells8010070","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,18]]}}}