Abstract
Intraflagellar transport (IFT) is essential for the formation and function of the microtubule-based primary cilium, which acts as a sensory and signalling device at the cell surface. Consisting of IFT-A/B and BBSome cargo adaptors that associate with molecular motors, IFT transports protein into (anterograde IFT) and out of (retrograde IFT) the cilium. In this study, we identify the mostly uncharacterised ERICH3 protein as a component of the mammalian primary cilium. Loss of ERICH3 causes abnormally short cilia and results in the accumulation of IFT-A/B proteins at the ciliary tip, together with reduced ciliary levels of retrograde transport regulators, ARL13B, INPP5E and BBS5. We also show that ERICH3 ciliary localisations require ARL13B and BBSome components. Finally, ERICH3 loss causes positive (Smoothened) and negative (GPR161) regulators of sonic hedgehog signaling (Shh) to accumulate at abnormally high levels in the cilia of pathway-stimulated cells. Together, these findings identify ERICH3 as a novel component of the primary cilium that regulates cilium length and the ciliary levels of Shh signaling molecules. We propose that ERICH3 functions within retrograde IFT-associated pathways to remove signaling proteins from cilia.
Highlights
The formation and maintenance of primary cilia is critically dependent on the cycling intraflagellar transport (IFT) system, which operates bidirectionally along the ciliary microtubules to deliver proteins to, and remove proteins from, the organelle
Intraflagellar transport (IFT) and associated cargo adaptors are thought to be critical for regulating the ciliary levels of various signaling molecules that function within the organelle
This is best understood for the Sonic hedgehog (Shh) pathway where various IFT-A, IFT-B and BBSome-associated proteins are linked to the ciliary targeting and removal of positive
Summary
The formation and maintenance of primary cilia is critically dependent on the cycling intraflagellar transport (IFT) system, which operates bidirectionally along the ciliary microtubules to deliver proteins to, and remove proteins from, the organelle. The IFT-A complex (6 proteins) is biochemically organised into core (IFT122/140/144) and non-core (IFT43/121/139) submodules, and regulates the ciliary tip formation of cargo-laden retrograde IFT trains, as well as the ciliary import of at least some membrane proteins Primary cilia are critically important for Shh signaling, where all of the key pathway components associate with the organelle, including the Patched[1] (PTCH1) receptor, positive (Smoothened; SMO) and negative (GPR161; SUFU) pathway regulators, and downstream Gli transcription factors that get processed to activator (GliA) or repressor (GliR) forms[51,52,53,54,55,56]. Our findings implicate ERICH3 as a novel component of retrograde IFT-associated pathways that remove Shh signaling regulators from cilia
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