Primary cilia proteins: ciliary and extraciliary sites and functions

Abstract

Primary cilia are immotile organelles known for their roles in development and cell signaling. Defects in primary cilia result in a range of disorders named ciliopathies. Because this organelle can be found singularly on almost all cell types, its importance extends to most organ systems. As such, elucidating the importance of the primary cilium has attracted researchers from all biological disciplines. As the primary cilia field expands, caution is warranted in attributing biological defects solely to the function of this organelle, since many of these "ciliary" proteins are found at other sites in cells and likely have non-ciliary functions. Indeed, many, if not all, cilia proteins have locations and functions outside the primary cilium. Extraciliary functions are known to include cell cycle regulation, cytoskeletal regulation, and trafficking. Cilia proteins have been observed in the nucleus, at the Golgi apparatus, and even in immune synapses of T cells (interestingly, a non-ciliated cell). Given the abundance of extraciliary sites and functions, it can be difficult to definitively attribute an observed phenotype solely to defective cilia rather than to some defective extraciliary function or a combination of both. Thus, extraciliary sites and functions of cilia proteins need to be considered, as well as experimentally determined. Through such consideration, we will understand the true role of the primary cilium in disease as compared to other cellular processes' influences in mediating disease (or through a combination of both). Here, we review a compilation of known extraciliary sites and functions of "cilia" proteins as a means to demonstrate the potential non-ciliary roles for these proteins.

Primary Cilia and Calcium Signaling Interactions

“…Although several connections to the cell cycle can be made through ciliary-localized proliferative pathways, the connection between primary cilia and the cell cycle lies in the dependence on the centrosome [ 76 , 77 ]. However, as both rely on the same organelle, they also are mutually exclusive processes that do not co-exist, and thus the cell is constantly teetering on which process to favor [ 76 ].…”

Moderate Fluid Shear Stress Regulates Heme Oxygenase-1 Expression to Promote Autophagy and ECM Homeostasis in the Nucleus Pulposus Cells

“…Primary cilium is a microtubule-based organelle, which extends as a solitary protrusion from the surface of most mammalian cell types, including NP cells (Zheng et al, 2018;Anvarian et al, 2019). It can sense and transmit extracellular mechanical and chemical signals, to regulate various cellular processes and maintain tissue homeostasis (Hua and Ferland, 2018;Kim and Kim, 2019). Because primary cilium cannot synthesize proteins, ciliumassociated trafficking proteins, such as IFT88, are therefore critical for cilium biogenesis, maintenance and function (Wang et al, 2016).…”

Tissue‐dependent differences in Bardet–Biedl syndrome gene expression

“…In recent years, there has been increasing interest in highlighting functions of ciliary proteins at extra‐ciliary sites and in non‐ciliary contexts. Such functions include intracellular trafficking, regulation of the cytoskeleton, mitosis, cell cycle regulation, regulation of the DNA damage response and transcriptional control [Vertii et al., ; Hua and Ferland, ]. Several studies also suggest that some of the BBS proteins might take on extra‐ciliary roles, possibly in a non BBSome/chaperonin dependent manner that could be relevant to the aetiology of the disorder [Novas et al., ].…”

“…Growing evidence suggests that cilia proteins also have alternative functions in ciliary independent mechanisms. Such extraciliary functions include cell cycle regulation, non‐ciliary trafficking, regulation of the DNA damage response, and transcriptional control [Vertii et al., ; Hua and Ferland, ]. In light of this, it is plausible that the BBSome and BBS chaperonin‐like proteins also have alternative functions, possibly in an individual protein dependent manner.…”