Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication
- University of California, San Francisco, United States
- Howard Hughes Medical Institute, Boston Children's Hospital, United States
- United Arab Emirates University, United Arab Emirates
- Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States
Abstract
Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene,CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. Thus, centriolar satellites build a MCPH complex critical for human neurodevelopment that promotes CDK2 centrosomal localization and centriole duplication.
Article and author information
Author details
Reviewing Editor
- W James Nelson, Stanford University, United States
Ethics
Human subjects: Subjects were identified and evaluated in a clinical setting for medical history, cognitive impairment and physical abnormalities. Peripheral blood samples were collected from the affected individuals and family members after obtaining written informed consent according to the protocols approved by the participating institutions and the ethical standards of the responsible national and institutional committees on human subject research.
Version history
- Received: March 18, 2015
- Accepted: August 21, 2015
- Accepted Manuscript published: August 22, 2015 (version 1)
- Accepted Manuscript updated: August 24, 2015 (version 2)
- Accepted Manuscript updated: September 2, 2015 (version 3)
- Version of Record published: September 18, 2015 (version 4)
Copyright
© 2015, Kodani et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,996
- Page views
-
- 1,257
- Downloads
-
- 103
- Citations
Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication
eLife 4:e07519.
https://doi.org/10.7554/eLife.07519
Further reading
-
- Cell Biology
High-altitude polycythemia (HAPC) affects individuals living at high altitudes, characterized by increased red blood cells (RBCs) production in response to hypoxic conditions. The exact mechanisms behind HAPC are not fully understood. We utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O2 to investigate these mechanisms. Our findings indicate that HH significantly boosts erythropoiesis, leading to erythrocytosis and splenic changes, including initial contraction to splenomegaly over 14 days. A notable decrease in red pulp macrophages (RPMs) in the spleen, essential for RBCs processing, was observed, correlating with increased iron release and signs of ferroptosis. Prolonged exposure to hypoxia further exacerbated these effects, mirrored in human peripheral blood mononuclear cells. Single-cell sequencing showed a marked reduction in macrophage populations, affecting the spleen’s ability to clear RBCs and contributing to splenomegaly. Our findings suggest splenic ferroptosis contributes to decreased RPMs, affecting erythrophagocytosis and potentially fostering continuous RBCs production in HAPC. These insights could guide the development of targeted therapies for HAPC, emphasizing the importance of splenic macrophages in disease pathology.
-
- Cell Biology
Mapping proteins in and associated with the Golgi apparatus reveals how this cellular compartment emerges in budding yeast and progresses over time.
