Cystatin B-deficiency triggers ectopic histone H3 tail cleavage during neurogenesis

Daura, Eduard; Tegelberg, Saara; Yoshihara, Masahito; Jackson, Christopher B.; Simonetti, Francesca; Aksentjeff, Katri; Ezer, Sini; Hakala, Paula; Katayama, Shintaro; Kere, Juha; Lehesjoki, Anna‐Elina; Joensuu, Tarja

doi:10.1016/j.nbd.2021.105418

Cited by 13 publications

(20 citation statements)

References 75 publications

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“…However, CSTBdeficient microglia show activated phenotype already at P14 and further studies are needed to clarify the relation of these observations. Combined, our previous and current findings indicate that CSTB prevents premature histone cleavage before neural stem cell differentiation (Daura et al, 2021), modulates the levels of H3cs1 throughout brain development and is an essential factor in suppressing H3cs1 after the second postnatal week until adulthood. This developmentally regulated mechanism could explain why the complete loss of CSTB disrupts embryonic brain development in humans, whereas residual cellular CSTB expression results in the milder phenotype of EPM1, with apparently normal early development and symptomatic onset in late childhood/early adolescence (Koskenkorva et al, 2011;Mancini et al, 2016;Lehesjoki and Kälviäinen, 2020).…”

Section: Discussionsupporting

confidence: 69%

“…The following TaqMan probes were used for target amplification: Cstb (Mm00432769_m1), Lmnb1 (Mm00521949_m1), Ywhaz (Mm03950126_s1), and Rpl13 (Mm02526700_g1). Cstb and Lmnb1 expression data was normalized to that of both Ywhaz and Rpl13 , chosen due to their stable expression in contexts of neural development ( Daura et al, 2021 ) and neurodegeneration ( Rydbirk et al, 2016 ), respectively. Relative gene expression was calculated using the 2 –ΔCt method.…”

Section: Methodsmentioning

confidence: 99%

“…In a human glioblastoma cell line, CSTB co-immunoprecipitated with histones and with the cysteine protease cathepsin L ( Čeru et al, 2010 ). In a model of in vitro neurogenesis, we previously reported that CSTB regulates the cysteine cathepsin mediated proteolytic processing of the N-terminal tail of histone H3 between amino acids Ala21 and Thr22 ( Daura et al, 2021 ), an evolutionarily conserved histone modification commonly known as H3 cleavage site 1 (H3cs1) ( Duncan et al, 2008 ; Santos-Rosa et al, 2009 ). In mammalian cells and tissues, upregulation of H3cs1 has been linked to chromatin reprogramming events such as cellular differentiation and senescence, through permanent removal of post-translational modifications from histone proteins ( Duarte et al, 2014 ; Azad et al, 2018 ; Cheung et al, 2021 ; Ferrari et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Cystatin B deficiency results in sustained histone H3 tail cleavage in postnatal mouse brain mediated by increased chromatin-associated cathepsin L activity

Daura

Tegelberg²,

Hakala³

et al. 2022

Front. Mol. Neurosci.

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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 in vitro 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 (wt) 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 de novo synthesized cathepsin L suggesting a role for nuclear cathepsin L in brain development and maturation. On the contrary, the brains of Cstb–/– 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 in vitro, we explored the presence of several cellular senescence markers in the maturing Cstb–/– cerebellum, where we see increased levels of H3cs1. While several markers showed alterations in Cstb–/– 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.

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Section: Discussionsupporting

confidence: 69%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cystatin B deficiency results in sustained histone H3 tail cleavage in postnatal mouse brain mediated by increased chromatin-associated cathepsin L activity

Daura

Tegelberg²,

Hakala³

et al. 2022

Front. Mol. Neurosci.

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“…In the nucleus, stefin B deficiency results in histone H3 N-terminus cleavage, exerted by cathepsins L and B (Daura et al, 2021). This cleavage results in significant transcriptional changes of the nuclear-encoded mitochondrial genes (Daura et al, 2021). Our team has previously demonstrated ( Čeru et al, 2010a) that stefin B in the nucleus interacts with nucleosomes, specifically with histones H2A.Z, H2B, and H3, as well as cathepsin L.…”

Section: Gene Protein Localization and Pathologymentioning

confidence: 89%

“…Stefin B protein is located in the cytosol, mitochondria, and nucleus of cells ( Čeru et al, 2010a). In the nucleus, stefin B deficiency results in histone H3 N-terminus cleavage, exerted by cathepsins L and B (Daura et al, 2021). This cleavage results in significant transcriptional changes of the nuclear-encoded mitochondrial genes (Daura et al, 2021).…”

Section: Gene Protein Localization and Pathologymentioning

confidence: 99%

Human stefin B: from its structure, folding, and aggregation to its function in health and disease

Žerovnik

2022

Front. Mol. Neurosci.

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Mutations in the gene for human stefin B (cystatin B) cause progressive myoclonic epilepsy type 1 (EPM1), a neurodegenerative disorder. The most common change is dodecamer repeats in the promoter region of the gene, though missense and frameshift mutations also appear. Human stefin B primarily acts as a cysteine cathepsin inhibitor, and it also exhibits alternative functions. It plays a protective role against oxidative stress, likely via reducing mitochondrial damage and thus generating fewer mitochondrial reactive oxygen species (ROS). Accordingly, lack of stefin B results in increased inflammation and NLRP3 inflammasome activation, producing more ROS. The protein is cytosolic but also has an important role in the nucleus, where it prevents cleavage of the N terminal part of histone 3 by inhibiting cathepsins L and B and thus regulates transcription and cell cycle. Furthermore, it has been shown that stefin B is oligomeric in cells and that it has a specific role in the physiology of the synapse and in vesicular transport. On the basis of my research team’s data on the structure, folding, and aggregation of stefin B, we have proposed that it might regulate proteostasis, possessing a chaperone-like function. In this review, I synthesize these observations and derive some conclusions on possible sources of EPM1 pathology. The interaction partners of stefin B and other gene mutations leading to EPM1-like pathology are discussed and common pathways are pinpointed.

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The micronuclear histone H3 clipping in the unicellular eukaryote Tetrahymena thermophila

Fan

Pan

Diao

et al. 2022

Mar Life Sci Technol

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Cystatin B-deficiency triggers ectopic histone H3 tail cleavage during neurogenesis

Cited by 13 publications

References 75 publications

Cystatin B deficiency results in sustained histone H3 tail cleavage in postnatal mouse brain mediated by increased chromatin-associated cathepsin L activity

Cystatin B deficiency results in sustained histone H3 tail cleavage in postnatal mouse brain mediated by increased chromatin-associated cathepsin L activity

Human stefin B: from its structure, folding, and aggregation to its function in health and disease

The micronuclear histone H3 clipping in the unicellular eukaryote Tetrahymena thermophila

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