Abstract
Ciliogenesis is generally inhibited in dividing cells, however, it has been unclear which signaling cascades regulate the phenomenon. Here, we report that epidermal growth factor receptor (EGFR) kinase suppresses ciliogenesis by directly phosphorylating the deubiquitinase USP8 on Tyr-717 and Tyr-810 in RPE1 cells. These phosphorylations elevate the deubiquitinase activity, which then stabilizes the trichoplein-Aurora A pathway, an inhibitory mechanism of ciliogenesis. EGFR knockdown and serum starvation result in ciliogenesis through downregulation of the USP8-trichoplein-Aurora A signal. Moreover, primary cilia abrogation, which is induced upon IFT20 or Cep164 depletion, ameliorates the cell cycle arrest of EGFR knockdown cells. The present data reveal that the EGFR-USP8-trichoplein-Aurora A axis is a critical signaling cascade that restricts ciliogenesis in dividing cells, and functions to facilitate cell proliferation. We further show that usp8 knockout zebrafish develops ciliopathy-related phenotypes including cystic kidney, suggesting that USP8 is a regulator of ciliogenesis in vertebrates.
Highlights
Ciliogenesis is generally inhibited in dividing cells, it has been unclear which signaling cascades regulate the phenomenon
We tested if overexpression of these DUBs could suppress the serum starvation-induced ciliogenesis in RPE1 cells (Supplementary Fig. 2)
USP8 expression levels were reported to become undetectable by serum starvation in WI-38 human fibroblasts[36], we found no change in RPE1 cells (Fig. 6a; upper panels)
Summary
Ciliogenesis is generally inhibited in dividing cells, it has been unclear which signaling cascades regulate the phenomenon. The presence of primary cilia has long been implicated in cell cycle progression: tissue culture cells generally form primary cilia when they are exposed to cell cycle exit signals such as serum starvation, and serum stimulation induces primary cilia disassembly that is accompanied by cell cycle re-entry[11,12] This mutually exclusive relationship between ciliogenesis and cell cycle progression is considered to allow centrosomes to duplicate and to function as the main microtubule-organizing centers and mitotic apparatuses in growing cells[3,6,13,14,15,16,17]. We further found that usp[8] knockout zebrafish developed ciliopathy-related anomalies, suggesting that USP8 functions as an important factor of ciliogenesis in vertebrates
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