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BACE2 degradation is mediated by both the proteasome and lysosome pathways.

ABSTRACT: BACKGROUND:Alzheimer's disease is the most common neurodegenerative disease in the elderly. Amyloid-? protein (A?) is the major component of neuritic plaques which are the hallmark of AD pathology. ?-site APP cleaving enzyme 1 (BACE1) is the major ?-secretase contributing to A? generation. ?-site APP-cleaving enzyme 2 (BACE2), the homolog of BACE1, might play a complex role in the pathogenesis of Alzheimer's disease as it is not only a ?-secretase but also a conditional ?-secretase. Dysregulation of BACE2 is observed in Alzheimer's disease. However, the regulation of BACE2 is less studied compared with BACE1, including its degradation pathways. In this study, we investigated the turnover rates and degradation pathways of BACE2 in both neuronal cells and non-neuronal cells. RESULTS:Both lysosomal inhibition and proteasomal inhibition cause a time- and dose-dependent increase of transiently overexpressed BACE2 in HEK293 cells. The half-life of transiently overexpressed BACE2 protein is approximately 6?h. Moreover, the half-life of endogenous BACE2 protein is approximately 4?h in both HEK293 cells and mouse primary cortical neurons. Furthermore, both lysosomal inhibition and proteasomal inhibition markedly increases endogenous BACE2 in HEK293 cells and mouse primary cortical neurons. CONCLUSIONS:This study demonstrates that BACE2 is degraded by both the proteasome and lysosome pathways in both neuronal and non-neuronal cells at endogenous level and in transient overexpression system. It indicates that BACE2 dysregulation might be mediated by the proteasomal and lysosomal impairment in Alzheimer's disease. This study advances our understanding of the regulation of BACE2 and provides a potential mechanism of its dysregulation in Alzheimer's disease.

SUBMITTER: Qiu K

PROVIDER: S-EPMC7066761 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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BACE2 degradation is mediated by both the proteasome and lysosome pathways.

Qiu Kaixin K Liang Wenping W Wang Shuai S Kong Tingting T Wang Xin X Li Chunyan C Wang Zhe Z Wu Yili Y

BMC molecular and cell biology 20200311 1

<h4>Background</h4>Alzheimer's disease is the most common neurodegenerative disease in the elderly. Amyloid-β protein (Aβ) is the major component of neuritic plaques which are the hallmark of AD pathology. β-site APP cleaving enzyme 1 (BACE1) is the major β-secretase contributing to Aβ generation. β-site APP-cleaving enzyme 2 (BACE2), the homolog of BACE1, might play a complex role in the pathogenesis of Alzheimer's disease as it is not only a θ-secretase but also a conditional β-secretase. Dysr ...[more]

PMID: 32160867

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Project description:BackgroundGlioma stem cells (GSCs) are considered the initial cells of gliomas, contributing to therapeutic resistance. Patient-derived GSCs well recapitulate the heterogeneity of their parent glioma tissues, which can be classified into different subtypes. Likewise, previous works identified GSCs as two distinct subtypes, mesenchymal (MES) and proneural (PN) subtypes, and with general recognition, the MES subtype is considered a more malignant phenotype characterized by high invasion and radioresistance. Therefore, understanding the mechanisms involved in the MES phenotype is necessary for glioblastoma treatment.MethodsData for bioinformatic analysis were obtained from The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) database. An antibody was used to block cell surface glucose-regulated protein 78 (csGRP78). Apoptosis and cell cycle analyses were performed to evaluate radiation damage. Immunofluorescence staining was applied to assess protein expression and distribution. Mass spectrometry combined with bioinformatic analysis was used to screen downstream molecules. Intracranial GSC-derived xenografts were established for in vivo experiments.ResultsTotal GRP78 expression was associated with MES GSC stemness, and csGRP78 was highly expressed in MES GSCs. Targeting csGRP78 suppressed the self-renewal and radioresistance of MES GSCs in vitro and in vivo, accompanied by downregulation of the STAT3, NF-κB and C/EBPβ pathways. Mass spectrometry revealed the potential downstream β-site APP-cleaving enzyme 2 (BACE2), which was regulated by csGRP78 via lysosomal degradation. Knockdown of BACE2 inactivated NF-κB and C/EBPβ and significantly suppressed the tumorigenesis and radioresistance of MES GSCs in vitro and in vivo.ConclusionsCell surface GRP78 was preferentially expressed in MES GSCs and played a pivotal role in MES phenotype maintenance. Thus, blocking csGRP78 in MES GSCs with a high-specificity antibody might be a promising novel therapeutic strategy.

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BACE2 degradation is mediated by both the proteasome and lysosome pathways.

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BACE2 degradation is mediated by both the proteasome and lysosome pathways.

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