{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T19:50:52Z","timestamp":1791575452220,"version":"4.3.4"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T00:00:00Z","timestamp":1669766400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Cystatin B (CSTB) is a cysteine cathepsin inhibitor whose biallelic loss-of-function mutations in human result in defects in brain development and in neurodegeneration. The physiological function of CSTB is largely unknown, and the mechanisms underlying the human brain diseases remain poorly understood. We previously showed that CSTB modulates the proteolysis of the N-terminal tail of histone H3 (H3cs1) during <jats:italic>in vitro<\/jats:italic> neurogenesis. Here we investigated the significance of this mechanism in postnatal mouse brain. Spatiotemporal analysis of H3cs1 intensity showed that while H3cs1 in wild-type (<jats:italic>wt<\/jats:italic>) mice was found at varying levels during the first postnatal month, it was virtually absent in adult brain. We further showed that the high level of H3cs1 coincides with chromatin association of <jats:italic>de novo<\/jats:italic> synthesized cathepsin L suggesting a role for nuclear cathepsin L in brain development and maturation. On the contrary, the brains of <jats:italic>Cstb<\/jats:italic><jats:sup>\u2013\/\u2013<\/jats:sup> mice showed sustained H3cs1 proteolysis to adulthood with increased chromatin-associated cathepsin L activity, implying that CSTB regulates chromatin-associated cathepsin L activity in the postnatal mouse brain. As H3 tail proteolysis has been linked to cellular senescence <jats:italic>in vitro<\/jats:italic>, we explored the presence of several cellular senescence markers in the maturing <jats:italic>Cstb<\/jats:italic><jats:sup>\u2013\/\u2013<\/jats:sup> cerebellum, where we see increased levels of H3cs1. While several markers showed alterations in <jats:italic>Cstb<\/jats:italic><jats:sup>\u2013\/\u2013<\/jats:sup> mice, the results remained inconclusive regarding the association of deficient CSTB function with H3cs1-induced senescence. Together, we identify a molecular role for CSTB in brain with implications for brain development and disease.<\/jats:p>","DOI":"10.3389\/fnmol.2022.1069122","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T05:46:50Z","timestamp":1669787210000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Cystatin B deficiency results in sustained histone H3 tail cleavage in postnatal mouse brain mediated by increased chromatin-associated cathepsin L activity"],"prefix":"10.3389","volume":"15","author":[{"given":"Eduard","family":"Daura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saara","family":"Tegelberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Hakala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Elina","family":"Lehesjoki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarja","family":"Joensuu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1204","article-title":"Structural basis for the recognition and cleavage of histone H3 by cathepsin L.","volume":"2","author":"Adams-Cioaba","year":"2011","journal-title":"Nat. Commun."},{"key":"B2","doi-asserted-by":"crossref","DOI":"10.1016\/j.yebeh.2021.108157","article-title":"Cognitive functioning in progressive myoclonus epilepsy type 1 (Unverricht-Lundborg Disease, EPM1).","volume":"122","author":"\u00c4iki\u00e4","year":"2021","journal-title":"Epilepsy Behav."},{"key":"B3","doi-asserted-by":"crossref","first-page":"3051","DOI":"10.1016\/j.jmb.2018.07.013","article-title":"Modifying chromatin by histone tail clipping.","volume":"430","author":"Azad","year":"2018","journal-title":"J Mol. Biol."},{"key":"B4","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.3390\/ijms15011554","article-title":"Phosphorylation of histone H2AX in the mouse brain from development to senescence.","volume":"15","author":"Barral","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2596","DOI":"10.1210\/en.2018-00220","article-title":"Comparing postnatal development of gonadal hormones and associated social behaviors in rats, mice, and humans.","volume":"159","author":"Bell","year":"2018","journal-title":"Endocrinology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"4172","DOI":"10.1128\/MCB.00135-06","article-title":"Cathepsin L stabilizes the histone modification landscape on the Y chromosome and pericentromeric heterochromatin.","volume":"26","author":"Bulynko","year":"2006","journal-title":"Mol. Cell Biol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.bbrc.2017.07.039","article-title":"Snail transcription factor NLS and importin \u03b21 regulate the subcellular localization of Cathepsin L and Cux1.","volume":"491","author":"Burton","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B8","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1373\/clinchem.2008.112797","article-title":"The MIQE guidelines: Minimum information for publication of quantitative real-time PCR experiments.","volume":"55","author":"Bustin","year":"2009","journal-title":"Clin. Chem."},{"key":"B9","doi-asserted-by":"publisher","first-page":"4031","DOI":"10.1242\/dev.106559","article-title":"Development of the cerebellum: Simple steps to make a \u2018little brain\u2019.","volume":"141","author":"Butts","year":"2014","journal-title":"Development"},{"key":"B10","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.nbd.2012.04.005","article-title":"Loss of cortical GABA terminals in Unverricht-Lundborg disease.","volume":"47","author":"Buzzi","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"B11","doi-asserted-by":"publisher","first-page":"10078","DOI":"10.1074\/jbc.M109.034793","article-title":"Stefin B interacts with histones and cathepsin L in the nucleus.","volume":"285","author":"\u010ceru","year":"2010","journal-title":"J. Biol. Chem."},{"key":"B12","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1038\/s41590-021-00928-y","article-title":"Repression of CTSG, ELANE and PRTN3-mediated histone H3 proteolytic cleavage promotes monocyte-to-macrophage differentiation.","volume":"22","author":"Cheung","year":"2021","journal-title":"Nat. Immunol."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0300-z","article-title":"Transcriptional repression of DNA repair genes is a hallmark and a cause of cellular senescence.","volume":"9","author":"Collin","year":"2018","journal-title":"Cell Death Dis."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2021.105418","article-title":"Cystatin B-deficiency triggers ectopic histone H3 tail cleavage during neurogenesis.","volume":"156","author":"Daura","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"B15","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1002\/dvdy.74","article-title":"Senescence-associated beta-galactosidase activity in the developing avian retina.","volume":"248","author":"de Mera-Rodriguez","year":"2019","journal-title":"Dev. Dyn."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.623175","article-title":"Is senescence-associated beta-galactosidase a reliable in vivo marker of cellular senescence during embryonic development?","volume":"9","author":"de Mera-Rodriguez","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"B17","doi-asserted-by":"crossref","first-page":"9363","DOI":"10.1073\/pnas.92.20.9363","article-title":"A biomarker that identifies senescent human cells in culture and in aging skin in vivo.","volume":"92","author":"Dimri","year":"1995","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/cddiscovery.2016.11","article-title":"Induction and inhibition of the pan-nuclear gamma-H2AX response in resting human peripheral blood lymphocytes after X-ray irradiation.","volume":"2","author":"Ding","year":"2016","journal-title":"Cell Death Discovery"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6210","article-title":"Histone H3.3 and its proteolytically processed form drive a cellular senescence programme.","volume":"5","author":"Duarte","year":"2014","journal-title":"Nat. Commun."},{"key":"B20","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.cell.2008.09.055","article-title":"Cathepsin L proteolytically processes histone H3 during mouse embryonic stem cell differentiation.","volume":"135","author":"Duncan","year":"2008","journal-title":"Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.cellsig.2018.01.012","article-title":"Cathepsin L promotes ionizing radiation-induced U251 glioma cell migration and invasion through regulating the GSK-3\u03b2\/CUX1 pathway.","volume":"44","author":"Fei","year":"2018","journal-title":"Cell Signal"},{"key":"B22","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1093\/nar\/gkaa1228","article-title":"Intestinal differentiation involves cleavage of histone H3 N-terminal tails by multiple proteases.","volume":"49","author":"Ferrari","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B23","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1091\/mbc.e11-10-0884","article-title":"Lamin B1 loss is a senescence-associated biomarker.","volume":"23","author":"Freund","year":"2012","journal-title":"Mol. Biol. Cell"},{"key":"B24","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1111\/febs.15570","article-title":"A guide to assessing cellular senescence in vitro and in vivo.","volume":"288","author":"Gonzalez-Gualda","year":"2021","journal-title":"FEBS J."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2020.570640","article-title":"Quantitative changes in the mitochondrial proteome of cerebellar synaptosomes from preclinical cystatin B-deficient mice.","volume":"13","author":"Gorski","year":"2020","journal-title":"Front. Mol. Neurosci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/s1097-2765(04)00209-6","article-title":"A cathepsin L isoform that is devoid of a signal peptide localizes to the nucleus in S phase and processes the CDP\/Cux transcription factor.","volume":"14","author":"Goulet","year":"2004","journal-title":"Mol. Cell"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-14009-0","article-title":"Spatially and temporally defined lysosomal leakage facilitates mitotic chromosome segregation.","volume":"11","author":"H\u00e4m\u00e4list\u00f6","year":"2020","journal-title":"Nat. Commun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2696.e9","DOI":"10.1016\/j.molcel.2022.05.023","article-title":"Single-cell epigenetic analysis reveals principles of chromatin states in H3.3-K27M gliomas.","volume":"82","author":"Harpaz","year":"2022","journal-title":"Mol. Cell"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109228","article-title":"Replicative senescence dictates the emergence of disease-associated microglia and contributes to A\u03b2 pathology.","volume":"35","author":"Hu","year":"2021","journal-title":"Cell Rep."},{"key":"B30","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1006\/bbrc.1998.9613","article-title":"Multiple processing of procathepsin L to cathepsin L in vivo.","volume":"252","author":"Ishidoh","year":"1998","journal-title":"Biochem. Biophys. Res, Commun."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13531","article-title":"Regulatory role of cathepsin L in induction of nuclear laminopathy in Alzheimer\u2019s disease.","volume":"21","author":"Islam","year":"2022","journal-title":"Aging Cell"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0089321","article-title":"Gene expression alterations in the cerebellum and granule neurons of Cstb\u2013\/\u2013 mouse are associated with early synaptic changes and inflammation.","volume":"9","author":"Joensuu","year":"2014","journal-title":"PLoS One"},{"key":"B33","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1159\/000323470","article-title":"Severer phenotype in Unverricht-Lundborg disease (EPM1) patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutation in the CSTB gene.","volume":"8","author":"Koskenkorva","year":"2011","journal-title":"Neurodegener. Dis."},{"key":"B34","first-page":"305","article-title":"Gamma-H2AX - a novel biomarker for DNA double-strand breaks.","volume":"22","author":"Kuo","year":"2008","journal-title":"In vivo"},{"key":"B35","article-title":"Progressive myoclonic epilepsy type 1","author":"Lehesjoki","year":"2020","journal-title":"GeneReviews<sup>\u00ae<\/sup>"},{"key":"B36","doi-asserted-by":"publisher","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":"B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003185","article-title":"Specialization of gene expression during mouse brain development.","volume":"9","author":"Liscovitch","year":"2013","journal-title":"PLoS Comput. Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"31736","DOI":"10.1074\/jbc.M114.609396","article-title":"A role for stefin B (cystatin B) in inflammation and endotoxemia.","volume":"289","author":"Maher","year":"2014","journal-title":"J. Biol. Chem."},{"key":"B39","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1212\/WNL.0000000000002422","article-title":"CSTB null mutation associated with microcephaly, early developmental delay, and severe dyskinesia.","volume":"86","author":"Mancini","year":"2016","journal-title":"Neurology"},{"key":"B40","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1148\/radiol.13122458","article-title":"White matter degeneration with Unverricht-Lundborg progressive myoclonus epilepsy: A translational diffusion-tensor imaging study in patients and cystatin B-deficient mice.","volume":"269","author":"Manninen","year":"2013","journal-title":"Radiology"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0090709","article-title":"Progressive volume loss and white matter degeneration in cstb-deficient mice: A diffusion tensor and longitudinal volumetry MRI study.","volume":"9","author":"Manninen","year":"2014","journal-title":"PLoS One"},{"key":"B42","first-page":"816.e1","article-title":"SnapShot: Cellular senescence pathways.","volume":"170","author":"Mart\u00ednez-Zamudio","year":"2017","journal-title":"Cell"},{"key":"B43","doi-asserted-by":"publisher","first-page":"4238","DOI":"10.1091\/mbc.e08-03-0291","article-title":"Nuclear cathepsin F regulates activation markers in rat hepatic stellate cells.","volume":"19","author":"Maubach","year":"2008","journal-title":"Mol. Biol. Cell"},{"key":"B44","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.neuron.2015.06.014","article-title":"Critical role of histone turnover in neuronal transcription and plasticity.","volume":"87","author":"Maze","year":"2015","journal-title":"Neuron"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26237198","article-title":"The phosphorylated form of the histone H2AX (gammaH2AX) in the brain from embryonic life to old age.","volume":"26","author":"Merighi","year":"2021","journal-title":"Molecules"},{"key":"B46","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/0014-4827(76)90336-0","article-title":"Increased nuclear sizes in senescent human diploid fibroblast cultures.","volume":"100","author":"Mitsui","year":"1976","journal-title":"Exp. Cell Res."},{"key":"B47","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.jneuroim.2014.11.018","article-title":"Microglial numbers attain adult levels after undergoing a rapid decrease in cell number in the third postnatal week.","volume":"278","author":"Nikodemova","year":"2015","journal-title":"J. Neuroimmunol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1038\/ejhg.2017.39","article-title":"Severe neurodegeneration, progressive cerebral volume loss and diffuse hypomyelination associated with a homozygous frameshift mutation in CSTB.","volume":"25","author":"O\u2019Brien","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"B49","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1002\/glia.22760","article-title":"Abnormal microglial activation in the Cstb(-\/-) mouse, a model for progressive myoclonus epilepsy. EPM1.","volume":"63","author":"Okuneva","year":"2015","journal-title":"Glia"},{"key":"B50","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1093\/brain\/awv379","article-title":"Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer\u2019s-like pathology.","volume":"139","author":"Olmos-Alonso","year":"2016","journal-title":"Brain"},{"key":"B51","doi-asserted-by":"publisher","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":"B52","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":"B53","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1080\/078538902320772124","article-title":"Reduced cystatin B activity correlates with enhanced cathepsin activity in progressive myoclonus epilepsy.","volume":"34","author":"Rinne","year":"2002","journal-title":"Ann. Med."},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2011.00005","article-title":"Morphological development of thick-tufted layer v pyramidal cells in the rat somatosensory cortex.","volume":"5","author":"Romand","year":"2011","journal-title":"Front. Neuroanat."},{"key":"B55","doi-asserted-by":"crossref","DOI":"10.1038\/srep37116","article-title":"Assessment of brain reference genes for RT-qPCR studies in neurodegenerative diseases.","volume":"6","author":"Rydbirk","year":"2016","journal-title":"Sci. Rep."},{"key":"B56","doi-asserted-by":"crossref","DOI":"10.1016\/j.mad.2022.111675","article-title":"Cellular senescence in the aging brain: A promising target for neurodegenerative diseases.","volume":"204","author":"Sahu","year":"2022","journal-title":"Mech. Ageing Dev."},{"key":"B57","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/nsmb.1534","article-title":"Histone H3 tail clipping regulates gene expression.","volume":"16","author":"Santos-Rosa","year":"2009","journal-title":"Nat. Struct. Mol. Biol."},{"key":"B58","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/978-3-030-00934-2_30","article-title":"Cell detection with star-convex polygons,\u201d","author":"Schmidt","year":"2018","journal-title":"Medical Image Computing and Computer Assisted Intervention - Miccai 2018, Pt Ii"},{"key":"B59","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/ncb1095","article-title":"Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks.","volume":"6","author":"Sedelnikova","year":"2004","journal-title":"Nat. Cell Biol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.4161\/cc.8.12.8865","article-title":"The apoptotic ring: A novel entity with phosphorylated histones H2AX and H2B and activated DNA damage response kinases.","volume":"8","author":"Solier","year":"2009","journal-title":"Cell Cycle"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1939","DOI":"10.1002\/j.1460-2075.1990.tb08321.x","article-title":"The refined 2.4 A X-ray crystal structure of recombinant human stefin B in complex with the cysteine proteinase papain: A novel type of proteinase inhibitor interaction.","volume":"9","author":"Stubbs","year":"1990","journal-title":"Embo J."},{"key":"B62","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1097\/NEN.0b013e31823e68e1","article-title":"Early microglial activation precedes neuronal loss in the brain of the Cstb-\/- mouse model of progressive myoclonus epilepsy, EPM1.","volume":"71","author":"Tegelberg","year":"2012","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"B63","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/0014-5793(91)80804-C","article-title":"The cystatins: Protein inhibitors of cysteine proteinases.","volume":"285","author":"Turk","year":"1991","journal-title":"FEBS Lett."}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2022.1069122\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T05:46:59Z","timestamp":1669787219000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2022.1069122\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,30]]},"references-count":63,"alternative-id":["10.3389\/fnmol.2022.1069122"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2022.1069122","relation":{},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,30]]},"article-number":"1069122"}}