The master cell cycle regulator APC-Cdc20 regulates ciliary length and disassembly of the primary cilium

Abstract

The primary cilium has an important role in signaling; defects in structure are associated with a variety of human diseases. Much of the most basic biology of this organelle is poorly understood, even basic mechanisms, such as control of growth and resorption. We show that the activity of the anaphase-promoting complex (APC), an E3 that regulates the onset of anaphase, destabilizes axonemal microtubules in the primary cilium. Furthermore, the metaphase APC co-activator, Cdc20, is specifically recruited to the basal body of primary cilia. Inhibition of APC-Cdc20 activity increases the ciliary length, while overexpression of Cdc20 suppresses cilium formation. APC-Cdc20 activity is required for the timely resorption of the cilium after serum stimulation. In addition, APC regulates the stability of axonemal microtubules through targeting Nek1, the ciliary kinase, for proteolysis. These data demonstrate a novel function of APC beyond cell cycle control and implicate critical role of ubiquitin-mediated proteolysis in ciliary disassembly.DOI: http://dx.doi.org/10.7554/eLife.03083.001

Genome-wide screen identifies novel machineries required for both ciliogenesis and cell cycle arrest upon serum starvation

“…For example, cilia-related roles of Anaphase-Promoting Complex (APC), which is a well-known ubiquitin E3 ligase in cell cycle control, have been suggested [40]. To induce cilia disassembly, APC/C CDC20 is activated when cells exit from the quiescent state [41]. In contrast, APC/C CDH1 is necessary for cilia assembly by ensuring the optimal level of ciliary proteins, such as Dishevelled, are present when cells enter the quiescent state [42].…”

Cilium assembly and disassembly

“…Similarly to CP110, trichoplein disappears from mother centrioles during ciliogenesis, and its depletion promotes aberrant cilium assembly in proliferating cells 57 . The process of ubiquitin-mediated protein degradation is required for cilium disassembly 58 , and trichoplein proteolysis is critical for the initiation of axoneme extension, indicating a similar requirement during cilium assembly 59,60 . Interestingly, a newly discovered protein, nuclear distribution element (NDE)-like 1 (Ndel1), functions in the trichoplein–Aurora-A pathway, and similarly to trichoplein depletion, loss of Ndel1 triggers aberrant ciliogenesis in growing cells 61 .…”

Targeting Cdc20 as a novel cancer therapeutic strategy

“…Further studies implicated Cdc20 in governing cellular apoptosis through regulating the stability of Mcl-1 (Harley et al, 2010) and Bim (Wan et al, 2014). Interestingly, Cdc20 has also been reported to play a key role in ciliary disassembly (Wang, W. et al, 2014) and brain development (Yang et al, 2007; Yang et al, 2009). In the following sections, we will summarize the different biological functions of Cdc20 in cell cycle progression, apoptosis, ciliary disassembly and brain development.…”

“…Remarkably, HDAC6 (histone deacetylase 6) promoted the polyubiquitination of Cdc20, activated Cdc20 activity, and enhanced the differentiation of dendrites, suggesting that Cdc20 is involved in neuronal connectivity and plasticity (Kim, A. H. et al, 2009). In addition to its role in neuronal differentiation, Wang et al discovered a novel role for APC Cdc20 beyond cell cycle control and apoptosis, and implicated its function in ciliary disassembly in part through regulating Nek1 stability (Wang, W. et al, 2014). Furthermore, Chun et al discovered that overexpression of Cdc20 enhanced polyubiquitination and proteosomal degradation of REV1, which is a specialized DNA polymerase for DNA repair (Chun et al, 2013).…”