Abstract
Centriolar satellites are non-membrane cytoplasmic granules that deliver proteins to centrosome during centrosome biogenesis and ciliogenesis. Centriolar satellites are highly dynamic during cell cycle or ciliogenesis and how they are regulated remains largely unknown. We report here that sorting nexin 17 (SNX17) regulates the homeostasis of a subset of centriolar satellite proteins including PCM1, CEP131, and OFD1 during serum-starvation-induced ciliogenesis. Mechanistically, SNX17 recruits the deubiquitinating enzyme USP9X to antagonize the mindbomb 1 (MIB1)-induced ubiquitination and degradation of PCM1. SNX17 deficiency leads to enhanced degradation of USP9X as well as PCM1 and disrupts ciliogenesis upon serum starvation. On the other hand, SNX17 is dispensable for the homeostasis of PCM1 and USP9X in serum-containing media. These findings reveal a SNX17/USP9X mediated pathway essential for the homeostasis of centriolar satellites under serum starvation, and provide insight into the mechanism of USP9X in ciliogenesis, which may lead to a better understating of USP9X-deficiency-related human diseases such as X-linked mental retardation and neurodegenerative diseases.
Highlights
Centrosome functions as microtubule-organizing center (MTOC), which is required for the organization of mitotic spindle apparatus in mitotic cells; while in resting cells, it regulates ciliogenesis [1]
To determine whether sorting nexin 17 (SNX17) is cell-autonomously required for ciliogenesis, we turn to the well-established RPE1 cell-based in vitro ciliogenesis model
Ciliogenesis was induced by serum starvation for 48 h, and cilia were visualized by immunofluorescence staining with an anti-acetylated tubulin antibody (Ac-Tub)
Summary
Centrosome functions as microtubule-organizing center (MTOC), which is required for the organization of mitotic spindle apparatus in mitotic cells; while in resting cells, it regulates ciliogenesis [1]. It has been reported that under cellular stress (UV or heat shock) induced ciliogenesis, MIB1 is inactivated in a p38-independent pathway, and suppression of ciliogenesis by MIB1 is removed [5]. Another possibility is that PCM1 is rescued from the MIB1-induced degradation by a deubiquitinating enzyme (DUB), and USP9X (ubiquitin-specific protease 9X) is such a candidate. USP9X is a DUB that is able to regulate the integrity of centriolar satellites in mitotic cells [6,7,8], while it remains to be established whether such a mechanism functions during serum-starvation-induced ciliogenesis
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