Structure and Function of the Ciliary Pore Complex

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 DESCRIPTION (provided by applicant): Cilia are microtubule-based organelles that are involved in multiple cellular processes including signaling and motility. Protein entry into cilia s a tightly regulated process and defects in cilia-localized proteins are felt to be a root cause of many ciliopathies that manifest as cystic kidney disease, retinitis pigmentosa and/or other defects. The entry of proteins into cilia appears to be controlled at the cilia base where a ciliar pore is hypothesized to exist. Our group has proposed that the ciliary pore is highly analogous to the nuclear pore in its molecular composition and regulatory mechanism. In particular, we have demonstrated that proteins known to be involved in nuclear trafficking - the small GTPase Ran, its binding partners the importins, and nucleoporins - are present at the base or within cilia and regulate protein entry into the ciliary compartment. Based on our Preliminary Data, we now propose a model where two distinct mechanisms regulate entry into the ciliary compartment: entry of cytosolic proteins is regulated by nucleoporins of the ciliary pore complex (CPC) and requires kinesin motors and intraflagellar transport (IFT) whereas entry of membrane proteins is regulated by molecules of the transition zone (TZ) and is IFT-independent. We will test this model using inducible inhibition of nucleoporin and kinesin motor function combined with live-cell, single-molecule, and super-resolution microscopy techniques. These studies will lead the field forward in understanding ciliary gating mechanisms and will make important inroads in defining the nature of the cilia pore and its relation to the nuclear pore.