Journal article
The X-linked intellectual disability gene product and E3 ubiquitin ligase KLHL15 degrades doublecortin proteins to constrain neuronal dendritogenesis
The Journal of biological chemistry, Vol.296, p.100082
11/16/2020
DOI: 10.1074/jbc.RA120.016210
PMCID: PMC7948412
PMID: 33199366
Abstract
Proper brain development and function requires finely controlled mechanisms for protein turnover and disruption of genes involved in proteostasis is a common cause of neurodevelopmental disorders. Kelch-like 15 (KLHL15) is a substrate adaptor for cullin3 (Cul3)-containing E3 ubiquitin ligases and KLHL15 gene mutations were recently described as a cause of severe X-linked intellectual disability (XLID). Here, we used a bioinformatics approach to identify a family of neuronal microtubule-associated proteins (MAPs) as KLHL15 substrates, which are themselves critical for early brain development. We biochemically validated doublecortin (DCX), also an X-linked disease protein, and doublecortin-like kinase 1 and 2 (DCLK1/2) as bona fide KLHL15 interactors and mapped KLHL15 interaction regions to their tandem DCX domains. Shared with two previously identified KLHL15 substrates, a FRY tripeptide at the C-terminal edge of the second DCX domain is necessary for KLHL15-mediated ubiquitination of DCX and DCLK1/2 and subsequent proteasomal degradation. Conversely, silencing endogenous KLHL15 markedly stabilizes these DCX domain-containing proteins and prolongs their half-life. Functionally, overexpression of KLHL15 in the presence of wild-type DCX reduces dendritic complexity of cultured hippocampal neurons, whereas neurons expressing FRY-mutant DCX are resistant to KLHL15. Collectively, our findings highlight the critical importance of the E3 ubiquitin ligase adaptor KLHL15 in proteostasis of neuronal MAPs and identify a regulatory network important for development of the mammalian nervous system.
Details
- Title: Subtitle
- The X-linked intellectual disability gene product and E3 ubiquitin ligase KLHL15 degrades doublecortin proteins to constrain neuronal dendritogenesis
- Creators
- Jianing Song - University of Iowa Carver College of Medicine, United StatesRonald A Merrill - University of Iowa Carver College of MedicineAndrew Y Usachev - University of Iowa Carver College of Medicine, United StatesStefan Strack - Dept of Pharmacology, University of Iowa Carver College of Medicine, United States
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.296, p.100082
- DOI
- 10.1074/jbc.RA120.016210
- PMID
- 33199366
- PMCID
- PMC7948412
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- United States
- Grant note
- R01 DK116624 / NIDDK NIH HHS R21 MH115673 / NIMH NIH HHS R21 MH113352 / NIMH NIH HHS
- Language
- English
- Date published
- 11/16/2020
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984068241702771
Metrics
21 Record Views