**1. Introduction**

Cilia are antenna-like structures that are present in a variety of vertebrate cells [1–6]. There are two broad classes of cilia: Motile and nonmotile cilia [1]. The nonmotile cilia are called primary cilia. Both motile and primary cilia contain receptors and channels that detect signals from extracellular cues, such as mechanical flow and chemical stimulation, and transduce them into the cell, where they contribute to the maintenance of proper development and homeostasis. Considering these functions, it is not surprising that dysregulation of cilia function can cause cancer and other diseases, including ciliopathies, which manifest as various disease phenotypes, such as congenital anomalies, neurodevelopmental disorders, and obesity [1,6–9].

The structure and function of cilia are dynamically and precisely regulated, enabling cells to proliferate, migrate, and differentiate in a spatiotemporally controlled manner [6,10]. The primary cilium is composed of three compartments: The basal body, the transition zone, and the axoneme [2]. The basal body is derived from the mother centriole. Both centrioles and basal body contain nine circularly arranged triplets of microtubules (A-, B-, and C-tubules). The axoneme consists of nine microtubule doublets projected from the A- and B-tubules of the basal body. A central pair of singlet microtubules is present (+2) and absent (+0) in motile and primary cilia, respectively [11–14]. Therefore, the axoneme of motile and primary cilia is described as 9 × 2 + 2 and 9 × 2 + 0, respectively. The transition zone is a short area located above the basal body characterized by Y-shaped fibers connecting the microtubule doublets to the ciliary membrane [15]. The structure of motile cilia is more complex [16]. The daughter centriole plays an important role in the formation of motile cilia [16,17].

Primary cilia are disassembled and assembled when cells enter mitosis and exit the cell cycle, respectively [18–20]. The formation of primary cilia starts with the binding of small cytoplasmic vesicles transported from the Golgi apparatus to the mother centriole and conversion from the mother centriole to the basal body. The basal body is then moved and anchored to the plasma membrane. Coiled-coil protein 110, a component of the inhibitory complex of ciliogenesis, is removed to initiate axoneme elongation [21,22]. The ciliary vesicle then fuses with the plasma membrane, and large amounts of tubulin are transported from the cytoplasm into the cilium to extend the axoneme [23]. Many signaling molecules are also transported from the cytoplasm into the cilium (anterograde) and from the cilium into the cytoplasm (retrograde) by kinesin and dynein, respectively, which are motor proteins that travel along the axoneme [24].

Various types of posttranslational modification, including phosphorylation, acetylation, and ubiquitination, are involved in the dynamic regulation of the structure and function of cilia [2,4–6,25]. Modification of proteins by attachment of ubiquitin, a highly conserved 76-amino-acid protein, is a critical step in targeting the selective degradation of proteins by proteasomes as part of the ubiquitin–proteasome system (UPS) [26]. Protein ubiquitination occurs in three steps. First, ubiquitin-activating enzymes (E1) bind to ubiquitin, which is expressed in all cell types; second, ubiquitin is transferred from E1 enzymes to ubiquitin-conjugating enzymes (E2); and finally, ubiquitin-ligating enzymes (E3) transfer the ubiquitin from E2 enzymes and ligate it to lysine residues on the target protein. To date, 2, approximately 40, and about 600 E1, E2, and E3 enzymes, respectively, have been identified in humans [26]. The selectivity of target protein ubiquitination is conferred by the combination of E2 and E3 enzymes. Protein ubiquitination is counteracted by deubiquitinase (DUB)-mediated removal of ubiquitin moieties from ubiquitinated proteins [27]. About 100 DUBs have been identified in humans. The balance between ubiquitination and deubiquitination of target proteins and their proteasomal degradation are tightly regulated processes, and dysregulation of the UPS has been detected in various disorders [28–30].

Several lines of evidence support a major role for the UPS in regulating the structure and function of cilia [4–6,31–35]. Here, we briefly review the role of cilia in phenotypes of ciliopathy and cancer. We then focus on the role of E3 ubiquitin ligases and DUBs in ciliogenesis, ciliopathy, and cancer, and sugges<sup>t</sup> that these enzymes may serve as novel therapeutic targets for the development of treatments for these disorders.

### **2. Roles of Cilia in Ciliopathy and Cancer**

Cilia play crucial roles in the development of vertebrates. In some cell types, cilia are present only transiently during a critical point in development [36], and the spatiotemporal dysregulation of cilia can therefore a ffect the development of many organ systems, including the central nervous, sensory, cardiovascular, digestive, metabolic, and skeletal systems [8,14,37,38]. These complex multisystem developmental disorders are collectively termed ciliopathies (Table 1).


### **Table 1.** The roles of cilia in ciliopathy phenotypes.
