Non-ciliary Roles of IFT Proteins in Cell Division and Polycystic Kidney Diseases

Abstract

Cilia are small organelles present at the surface of most differentiated cells where they act as sensors for mechanical or biochemical stimuli. Cilia assembly and function require the Intraflagellar Transport (IFT) machinery, an intracellular transport system that functions in association with microtubules and motors. If IFT proteins have long been studied for their ciliary roles, recent evidences indicate that their functions are not restricted to the cilium. Indeed, IFT proteins are found outside the ciliary compartment where they are involved in a variety of cellular processes in association with non-ciliary motors. Recent works also provide evidence that non-ciliary roles of IFT proteins could be responsible for the development of ciliopathies related phenotypes including polycystic kidney diseases. In this review, we will discuss the interactions of IFT proteins with microtubules and motors as well as newly identified non-ciliary functions of IFT proteins, focusing on their roles in cell division. We will also discuss the potential contribution of non-ciliary IFT proteins functions to the etiology of kidney diseases.

Keywords: cell division; ciliopathies; intraflagellar transport; microtubule – associated proteins; molecular motor.

FIGURE 1

IFT complex overall organization and interactions with cytoskeleton components and mitotic motors. IFT proteins are divided into 2 classes. IFT-A complex is made of 6 subunits IFT144-140-139-122-121-43 where IFT144-140-122 form the core complex (Mukhopadhyay et al., 2010; Behal et al., 2012) and IFT139-120-43 form a peripheral subcomplex (Hirano et al., 2017). IFT-B complex is made of 16 subunits, and its overall architecture determined by VIP (visible immunoprecipitation) assays (Katoh et al., 2016), X-ray (Taschner et al., 2016), and interactome analysis (Boldt et al., 2016) reveals the presence of two stable subcomplexes. IFT-B1 is salt stable, its core complex is made of 9 subunits IFT88-81-74-70-52-46-27-25-22 (Lucker et al., 2005; Wang et al., 2009; Bhogaraju et al., 2011; Taschner et al., 2014; Wachter et al., 2019), while IFT-B2 is the peripheral complex made of 6 subunits IFT172-80-57-54-38-20 (Baker et al., 2003; Krock and Perkins, 2008; Taschner et al., 2016, 2018). The IFT-B2 central dimer IFT57-38 in association with the N-terminal domain of IFT52 and IFT88 mediates the interaction between both IFT-B subcomplexes (Taschner et al., 2016). Within IFT-B1, a stable tetrameric complex made of IFT88-70-52-46 was identified (Lucker et al., 2010; Taschner et al., 2011, 2014). Interactions between IFT machinery and mitotic motors are mediated by this tetramer (Delaval et al., 2011; Taulet et al., 2017; Vitre et al., 2020). Interactions with cytoskeleton components are mainly mediated by the IFT-B core complex, although the member of the IFT-A complex IFT139 is proposed to be a microtubule/tubulin binding partner (see text for details). Solid lines between IFT proteins indicate validated interactions, while dashed lines indicate putative interactions.

FIGURE 2

IFT proteins function throughout the cell cycle in association with microtubules and motors. IFT proteins contribute to a variety of interphase and mitotic molecular mechanisms. IFT proteins are required for ciliogenesis and for the regulation of cytoplasmic microtubules which were both linked to ciliopathies related phenotypes. Novel non-ciliary mechanisms for IFT proteins in mitosis have been identified. Perturbation of those mechanisms may also be linked to developmental defects and diseases. MTs, microtubules; CHR, chromosome.