Composition, organization and mechanisms of the transition zone, a gate for the cilium

Abstract

The cilium evolved to provide the ancestral eukaryote with the ability to move and sense its environment. Acquiring these functions required the compartmentalization of a dynein-based motility apparatus and signaling proteins within a discrete subcellular organelle contiguous with the cytosol. Here, we explore the potential molecular mechanisms for how the proximal-most region of the cilium, termed transition zone (TZ), acts as a diffusion barrier for both membrane and soluble proteins and helps to ensure ciliary autonomy and homeostasis. These include a unique complement and spatial organization of proteins that span from the microtubule-based axoneme to the ciliary membrane; a protein picket fence; a specialized lipid microdomain; differential membrane curvature and thickness; and lastly, a size-selective molecular sieve. In addition, the TZ must be permissive for, and functionally integrates with, ciliary trafficking systems (including intraflagellar transport) that cross the barrier and make the ciliary compartment dynamic. The quest to understand the TZ continues and promises to not only illuminate essential aspects of human cell signaling, physiology, and development, but also to unravel how TZ dysfunction contributes to ciliopathies that affect multiple organ systems, including eyes, kidney, and brain.

Male germ cell-associated kinase (MAK) is required for axoneme formation during ciliogenesis in zebrafish photoreceptors

“…Eyes shut (EYS) is a secreted extracellular matrix protein localized near at the transition zone of photoreceptors and required for the ciliary pocket formation in zebrafish (Yu et al, 2016). CEP290 (also known as NPHP6) is a large multidomain coiled coil protein localized at the proximal part of the transition zone (Goncalves and Pelletier, 2017; Park and Leroux, 2022). Genetic mutations of CEP290 are associated with Leber’s congenital amaurosis in humans (den Hollander et al, 2006) and photoreceptor degeneration in zebrafish (Cardenas-Rodriguez et al, 2021).…”

“…In either case, the first step of ciliogenesis is the removal of CP110 from a distal appendage of the mother centriole, which enables ARL13b and components of IFT-A and IFT-B to assemble at the apical surface of a distal appendage of the mother centriole in a rab8-dependent manner (Breslow and Holland, 2019; Ge et al, 2022). The second step is formation of the transition zone by the transport of MKS and NPHP module components (Park and Leroux, 2022). The third step is extension of the axoneme through IFT-mediated ciliary transport, which transports and adds α-/μ-tubulin dimers to the plus end of the microtubule comprising the axoneme (Brouhard and Rice, 2018; Ge et al, 2022; Nakayama and Katoh, 2018).…”

“…The connecting cilium bridges the IS and the OS, through which phototransduction molecules are transported from the ER, then to the Golgi and into the OS. Importantly, the connecting cilium is equivalent to the transition zone in other cell types and functions as a gating system (Park and Leroux, 2022), through which OS resident proteins are sorted and transported to the OS by the intraflagellar transport (IFT) complex (Klena and Pigino, 2022) and BBSome, composed of eight Bardet-Biedl syndrome (BBS) proteins (Tian et al, 2023).…”

BBSome-dependent ciliary Hedgehog signaling governs cell fate in the white adipose tissue

“…Protein transport in and out of the cilium is conveyed via the intraflagellar transport (IFT) machinery (Mill et al, 2023). Furthermore, the BBSome protein complex, formed by BBS proteins, functions as an adaptor for retrograde transport out of the cilium (Nachury, 2018), and the transition zone (TZ) controls lateral diffusion of membrane proteins at the ciliary base (Park and Leroux, 2022). Together, the IFT, the BBSome, and the TZ determine the protein composition of the primary cilium.…”

Centriole and transition zone structures in photoreceptor cilia revealed by cryo-electron tomography

“…At the distal end of the CC (the base of the OS), the light-sensing discs are formed. The region at the base of cilia where the microtubules undergo a transition from triplets to doublets is often referred to as the transition zone (TZ), and its unique complement of proteins is thought to regulate trafficking through the region, performing a “gate” function (Park and Leroux, 2022). In mouse rods, only a subset of TZ proteins are restricted to the base of the CC, with most of those found beyond the triplet-to-doublet transition, whereas others, such as CEP290 (Potter et al, 2021) and SPATA7 (Dharmat et al, 2018) are distributed throughout the entire length of the CC, suggesting the entire CC may contribute to the gate function.…”