The ubiquitin E3 ligase NOSIP modulates protein phosphatase 2A activity in craniofacial development
Open accessAbstract
Holoprosencephaly is a common developmental disorder in humans characterised by incomplete brain hemisphere separation and midface anomalies. The etiology of holoprosencephaly is heterogeneous with environmental and genetic causes, but for a majority of holoprosencephaly cases the genes associated with the pathogenesis could not be identified so far. Here we report the generation of knockout mice for the ubiquitin E3 ligase NOSIP. The loss of NOSIP in mice causes holoprosencephaly and facial anomalies including cleft lip/palate, cyclopia and facial midline clefting. By a mass spectrometry based protein interaction screen we identified NOSIP as a novel interaction partner of protein phosphatase PP2A. NOSIP mediates the monoubiquitination of the PP2A catalytic subunit and the loss of NOSIP results in an increase in PP2A activity in craniofacial tissue in NOSIP knockout mice. We conclude, that NOSIP is a critical modulator of brain and craniofacial development in mice and a candidate gene for holoprosencephaly in humans.
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Loss of NOSIP caused perinatal lethality and holoprosencephaly, a severe impairment in craniofacial development often associated with defective Hedgehog signaling.
“Loss of NOSIP caused perinatal lethality and holoprosencephaly, a severe impairment in craniofacial development that is often associated with defective Hedgehog signaling.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [46]
NOSIP interacts with the C, Aα and B55α subunits, and in vivo loss of NOSIP led to an increase in PP2A activity specifically in palatal and facial tissue.
“NOSIP interacts with the C, Aα and B55α subunits, and in vivo loss of NOSIP lead to an increase in PP2A activity, specifically in palatal and facial tissue.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [46]
NOSIP is a ubiquitin E3 ligase that post-translationally modifies PP2A-C.
“Another protein that has been shown to post-translationally modify PP2A-C, is nitric oxide synthase interacting protein (NOSIP), a ubiquitin E3 ligase [46].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [46]
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Protein Serine/Threonine Phosphatases: Keys to Unlocking Regulators and Substrates
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Physiologic functions of PP2A: Lessons from genetically modified mice
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- Authors
- Hoffmeister, M., Prelle, C., Küchler, P., Kovacevic, I., Moser, M., Müller-Esterl, W., & Oess, S.
- Affiliations
- Goethe University Frankfurt (DE)
- Max Planck Institute of Biochemistry (DE)
- Corresponding author
- Oess, Stefanie
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-12-29
- Volume
- 9
- Issue
- 12
- Pages
- e116150
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4278855
- OpenAlex
- W2031702489
- Cited by
- 21
- References
- 65
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 3 · 2021: 3 · 2019: 2 · 2018: 4 · 2017: 2 · 2016: 3
- FWCI
- 1.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Max Planck Digital Library (submittedVersion, other-oa)
- Figshare (submittedVersion, cc-by)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft (SFB,834)
- Adolf Messer Stiftung
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Cleft Lip and Palate Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- E3 ubiquitin ligase, protein phosphatase 2A, holoprosencephaly, craniofacial development, monoubiquitination, PP2A catalytic subunit, cleft lip and palate, cyclopia, knockout mice, candidate genes
- MeSH terms
- Animals, Animals, Newborn, Cleft Palate, Face, Methylation, Mice, Inbred C57BL, Protein Binding, Skull, Holoprosencephaly, Mice, Knockout, Catalytic Domain, Ubiquitin-Protein Ligases, Protein Phosphatase 2, Ubiquitination
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