Abstract
The primary cilium is required for Hedgehog signaling. So far, all known ciliogenic proteins regulate Hedgehog signaling through their role in ciliogenesis. Here we show that the mouse DZIP1 regulates Hedgehog signaling through two mechanisms. First, DZIP1 interacts with GLI3, a transcriptional regulator for Hedgehog signaling, and prevents GLI3 from entering the nucleus. Second, DZIP1 is required for ciliogenesis. We show that DZIP1 colocalizes and interacts with CEP164, a protein localizing at appendages of the mother centrioles, and IFT88, a component of the intraflagellar transport (IFT) machinery. Functionally, both CEP164 and Ninein appendage proteins fail to localize to ciliary appendages in Dzip1 mutant cells; IFT components are not recruited to the basal body of cilia. Importantly, the accumulation of GLI3 in the nucleus is independent of loss of primary cilia in Dzip1 mutant cells. Therefore, DZIP1 is the first known ciliogenic protein that regulates Hedgehog signaling through a dual mechanism and that biochemically links IFT machinery with Hedgehog pathway components.
Highlights
All known cilia-related proteins regulate Hedgehog signaling through their role in ciliogenesis
We show that DZIP1 colocalizes and interacts with CEP164, a protein localizing at appendages of the mother centrioles, and IFT88, a component of the intraflagellar transport (IFT) machinery
DZIP1 regulates Hh signaling through two mechanisms
Summary
All known cilia-related proteins regulate Hedgehog signaling through their role in ciliogenesis. Only KIF7, a kinesin motor and core component of the Hh cytoplasmic signaling complex, and MIM, a protein enriched in the basal body, have been shown to associate with GLI proteins physically (7, 19 –21), the in vivo role of MIM in Hh signaling and ciliogenesis needs to be further determined [22]. None of these proteins have far been biochemically shown to bridge Hh pathway components and IFT machinery. DZIP1 is the first known protein that regulates Hh signaling through this dual mechanism and biochemically connects Hh signaling components with IFT machinery
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