Journal
JOURNAL OF CELL BIOLOGY
Volume 218, Issue 7, Pages 2185-2197Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201803041
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Funding
- Charles Hood Foundation
- William Randolph Hearst Fund
- National Institutes of Health [1R21NS104633-01A1, R01 GM114119, R01 AR054396, GM095941]
- American Cancer Society [129742-RSG-16-156001-CCG]
- National Institute of Neurological Disorders and Stroke [R01 NS035129, R01 NS32457]
- Manton Center for Orphan Disease Research
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In mammals, centrioles participate in brain development, and human mutations affecting centriole duplication cause microcephaly. Here, we identify a role for the mammalian homologue of yeast SFI1, involved in the duplication of the yeast spindle pole body, as a critical regulator of centriole duplication in mammalian cells. Mammalian SFI1 interacts with USP9X, a deubiquitylase associated with human syndromic mental retardation. SFI1 localizes USP9X to the centrosome during S phase to deubiquitylate STIL, a critical regulator of centriole duplication. USP9X-mediated deubiquitylation protects STIL from degradation. Consistent with a role for USP9X in stabilizing STIL, cells from patients with USP9X loss-of-function mutations have reduced STIL levels. Together, these results demonstrate that SFI1 is a centrosomal protein that localizes USP9X to the centrosome to stabilize STIL and promote centriole duplication. We propose that the USP9X protection of STIL to facilitate centriole duplication underlies roles of both proteins in human neurodevelopment.
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