Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites

Abstract

The primary cilium is a microtubule-based organelle that functions in sensory and signaling pathways. Defects in ciliogenesis can lead to a group of genetic syndromes known as ciliopathies1–3. However, the regulatory mechanisms of primary ciliogenesis in normal and cancer cells are incompletely understood. Here, we demonstrate that autophagic degradation of a ciliopathy protein OFD1 (oral-facial-digital syndrome 1) at centriolar satellites promotes primary cilium biogenesis. Autophagy is a catabolic pathway in which cytosol, damaged organelles, and protein aggregates are engulfed in autophagosomes and delivered to lysosomes for destruction4. We show that the population of OFD1 at the centriolar satellites is rapidly degraded by autophagy upon serum starvation. In autophagy-deficient Atg5 or Atg3 null mouse embryonic fibroblasts, Ofd1 accumulates at centriolar satellites, leading to fewer and shorter primary cilia and a defective recruitment of BBS4 (Bardet-Biedl syndrome 4) to cilia. These defects are fully rescued by Ofd1 partial knockdown that reduces the population of Ofd1 at the centriolar satellites. More strikingly, OFD1 depletion at centriolar satellite promotes cilia formation in both cycling cells and transformed breast cancer MCF7 cells that normally do not form cilia. This work reveals that removal of OFD1 by autophagy at centriolar satellites represents a general mechanism to promote ciliogenesis in mammalian cells. These findings define a newly recognized role of autophagy in organelle biogenesis.

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

“…To gain insight into how CPAP coordinates cilium disassembly, we tested whether CPAP could interact with proteins, which are known to play roles in cilium disassembly such as Nde‐1, Aurora A, HDAC6 and OFD1 (Pugacheva et al , 2007; Kim et al , 2011; Tang et al , 2013; hereafter referred to as Cilium Disassembly Complex, CDC). Indeed, cytoplasmic CPAP co‐immunopurified with components of the CDC (CPAP‐CDC; Fig 3A).…”

Autophagy and regulation of cilia function and assembly

“…7 A role for autophagy in ciliogenesis and control of cilia length has also been demonstrated. [7][8][9] The aim of this review is to present the recent findings that uncover the interplay between cilia and autophagy and to discuss their potential impact on cell homeostasis and oncilia-related disease.…”

“…Autophagy has been shown to degrade components essential for ciliogenesis, such as IFT20, and also negative regulators of ciliogenesis such as the centriolar satellite protein OFD1 (see Figure 1). 9 This allows the autophagic process to control the length of the PC in response to the environmental changes. The degradation of IFT20 occurs predominantly via basal autophagy, 7 and that of OFD1 is observed early during serum starvation-induced autophagy.…”

“…7,9 Differences in the state of confluence of the cells -known to influence ciliogenesis -could be behind the discrepant findings. More broadly, additional studies are needed to determine the influence of the physiological context on the interplay between PC-related signaling and the autophagic pathway.…”

Autophagy is required for ectoplasmic specialization assembly in sertoli cells

“…20 Autophagy participates in cell growth, adaptation to stress conditions, anti-aging mechanisms, intracellular quality control, renovation during development and differentiation and the biogenesis of organelles such as cilia and acrosome. 21,[23][24][25] Autophagy is also active in Sertoli cells, [26][27][28][29] where it is involved in the clearance of SHBG/ABP that is selectively regulated by testosterone. 26 However, the role of autophagy in Sertoli cells is still largely unknown.…”