Dataset Information

APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain.

ABSTRACT: Neurodevelopmental cognitive disorders provide insights into mechanisms of human brain development. Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC). In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates. In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons. Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20, leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting that APC7 is required for the function of Cdh1-APC in the brain. Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin. Our findings define an essential function for APC7 and Cdh1-APC in neuronal heterochromatin regulation, with implications for understanding human brain development and disease.

SUBMITTER: Ferguson CJ

PROVIDER: S-EPMC8741739 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain.

Ferguson Cole J CJ Urso Olivia O Bodrug Tatyana T Gassaway Brandon M BM Watson Edmond R ER Prabu Jesuraj R JR Lara-Gonzalez Pablo P Martinez-Chacin Raquel C RC Wu Dennis Y DY Brigatti Karlla W KW Puffenberger Erik G EG Taylor Cora M CM Haas-Givler Barbara B Jinks Robert N RN Strauss Kevin A KA Desai Arshad A Gabel Harrison W HW Gygi Steven P SP Schulman Brenda A BA Brown Nicholas G NG Bonni Azad A

Molecular cell 20211222 1

Neurodevelopmental cognitive disorders provide insights into mechanisms of human brain development. Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC). In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates. In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-ass ...[more]

PMID: 34942119

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Project description:BackgroundThe nuclear lamina is a key determinant of nuclear architecture, integrity and functionality in metazoan nuclei. Mutations in the human lamin A gene lead to highly debilitating genetic diseases termed as laminopathies. Expression of lamin A mutations or reduction in levels of endogenous A-type lamins leads to nuclear defects such as abnormal nuclear morphology and disorganization of heterochromatin. This is accompanied by increased proteasomal degradation of certain nuclear proteins such as emerin, nesprin-1α, retinoblastoma protein and heterochromatin protein 1 (HP1). However, the pathways of proteasomal degradation have not been well characterized.Methodology/principal findingsTo investigate the mechanisms underlying the degradation of HP1 proteins upon lamin misexpression, we analyzed the effects of shRNA-mediated knock-down of lamins A and C in HeLa cells. Cells with reduced levels of expression of lamins A and C exhibited proteasomal degradation of HP1α and HP1β but not HP1γ. Since specific ubiquitin ligases are upregulated in lamin A/C knock-down cells, further studies were carried out with one of these ligases, RNF123, which has a putative HP1-binding motif. Ectopic expression of GFP-tagged RNF123 directly resulted in degradation of HP1α and HP1β. Mutational analysis showed that the canonical HP1-binding pentapeptide motif PXVXL in the N-terminus of RNF123 was required for binding to HP1 proteins and targeting them for degradation. The role of endogenous RNF123 in the degradation of HP1 isoforms was confirmed by RNF123 RNAi experiments. Furthermore, FRAP analysis suggested that HP1β was displaced from chromatin in laminopathic cells.Conclusions/significanceOur data support a role for RNF123 ubiquitin ligase in the degradation of HP1α and HP1β upon lamin A/C knock-down. Hence lamin misexpression can cause degradation of mislocalized proteins involved in key nuclear processes by induction of specific components of the ubiquitin-proteasome system.

Dataset Information

APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain.

Publications

APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain.

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