Ciliary transition zone (TZ) proteins RPGR and CEP290: role in photoreceptor cilia and degenerative diseases

Abstract

Introduction: Primary cilia are microtubule-based extensions of the plasma membrane in nearly all cell types. In vertebrate photoreceptors, the sensory cilium develops as outer segment (OS) that contains the photopigment rhodopsin and other proteins necessary for phototransduction. The distinct composition of proteins and lipids in the OS membrane is maintained by the selective barrier located at the border between the basal body and the ciliary compartment, called the transition zone (TZ).

Areas covered: In this review, we will discuss the identification and function of two ciliary TZ proteins, RPGR (retinitis pigmentosa GTPase regulator) and CEP290. Mutations in these proteins account for a majority of retinopathies due to ciliary dysfunction. We will also discuss the potential of such information in designing therapeutic approaches to treat cilia-dependent photoreceptor degenerative diseases.

Expert opinion: RPGR and CEP290 perform overlapping yet distinct functions in regulating trafficking of cargo via the TZ of photoreceptors. While RPGR modulates the trafficking by acting as a GEF for the small GTPase RAB8A, CEP290 may be involved in maintaining the polarized distribution of proteins in the OS by modulating intracellular levels of selected proteins involved in inhibiting OS formation.

Figure 1. Schematic representation of a rod photoreceptor

The polarized nature of the photoreceptors is represented by an elaborate generation of a distinct membrane component called the outer segment. This compartment contains membranous discs and is generated from the basal body (BB) in the apical inner segment. The region between the axoneme and the BB is called the connecting cilium (CC) or transition zone (TZ). A detailed schematic representation of the CC/TZ of photoreceptors shows the presence of Y-linkers that connect the ciliary microtubules to the plasma membrane. This region acts as a gate to selectively regulate trafficking of proteins to the OS.

Figure 2. Model of involvement of discrete multiprotein complexes of RPGR and CEP290/NPHP6 in photoreceptor cilia

The transition zone (TZ) of photoreceptors is largely composed of several protein complexes involved in degenerative disease. They form distinct complexes that may mediate sorting and trafficking of specific cargo to the OS. RPGRIP1 anchors RPGR at the TZ. The cargo is transported via the IFT particle.