CLEC16A interacts with retromer and TRIM27, and its loss impairs endosomal trafficking and neurodevelopment.
Animals
Humans
Actins
DNA-Binding Proteins
/ metabolism
Endosomes
/ genetics
HEK293 Cells
Lectins, C-Type
/ genetics
Membrane Proteins
/ metabolism
Monosaccharide Transport Proteins
/ chemistry
Nuclear Proteins
/ metabolism
Protein Transport
Transcription Factors
/ metabolism
Ubiquitin-Protein Ligases
/ genetics
Ubiquitins
/ metabolism
Zebrafish
/ genetics
Journal
Human genetics
ISSN: 1432-1203
Titre abrégé: Hum Genet
Pays: Germany
ID NLM: 7613873
Informations de publication
Date de publication:
Mar 2023
Mar 2023
Historique:
received:
21
09
2022
accepted:
09
12
2022
pubmed:
21
12
2022
medline:
3
3
2023
entrez:
20
12
2022
Statut:
ppublish
Résumé
CLEC16A is a membrane-associated C-type lectin protein that functions as a E3-ubiquitin ligase. CLEC16A regulates autophagy and mitophagy, and reportedly localizes to late endosomes. GWAS studies have associated CLEC16A SNPs to various auto-immune and neurological disorders, including multiple sclerosis and Parkinson disease. Studies in mouse models imply a role for CLEC16A in neurodegeneration. We identified bi-allelic CLEC16A truncating variants in siblings from unrelated families presenting with a severe neurodevelopmental disorder including microcephaly, brain atrophy, corpus callosum dysgenesis, and growth retardation. To understand the function of CLEC16A in neurodevelopment we used in vitro models and zebrafish embryos. We observed CLEC16A localization to early endosomes in HEK293T cells. Mass spectrometry of human CLEC16A showed interaction with endosomal retromer complex subunits and the endosomal ubiquitin ligase TRIM27. Expression of the human variant leading to C-terminal truncated CLEC16A, abolishes both its endosomal localization and interaction with TRIM27, suggesting a loss-of-function effect. CLEC16A knockdown increased TRIM27 adhesion to early endosomes and abnormal accumulation of endosomal F-actin, a sign of disrupted vesicle sorting. Mutagenesis of clec16a by CRISPR-Cas9 in zebrafish embryos resulted in accumulated acidic/phagolysosome compartments, in neurons and microglia, and dysregulated mitophagy. The autophagocytic phenotype was rescued by wild-type human CLEC16A but not the C-terminal truncated CLEC16A. Our results demonstrate that CLEC16A closely interacts with retromer components and regulates endosomal fate by fine-tuning levels of TRIM27 and polymerized F-actin on the endosome surface. Dysregulation of CLEC16A-mediated endosomal sorting is associated with neurodegeneration, but it also causes accumulation of autophagosomes and unhealthy mitochondria during brain development.
Identifiants
pubmed: 36538041
doi: 10.1007/s00439-022-02511-3
pii: 10.1007/s00439-022-02511-3
pmc: PMC9950183
doi:
Substances chimiques
Actins
0
CLEC16A protein, human
0
DNA-Binding Proteins
0
Lectins, C-Type
0
Membrane Proteins
0
Monosaccharide Transport Proteins
0
Nuclear Proteins
0
Transcription Factors
0
TRIM27 protein, human
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Ubiquitins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
379-397Subventions
Organisme : ZonMw
ID : #9127045
Pays : Netherlands
Organisme : ZonMw
ID : #9127045
Pays : Netherlands
Informations de copyright
© 2022. The Author(s).
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