Maxence V. Nachury
Molecular Mechanisms of Primary Cilium Assembly and FunctionOur laboratory investigates the molecular principles of primary cilium assembly and function. Shaped like an antenna projecting out of the cell, the primary cilium exposes receptors for diverse stimuli (like platelet-derived growth factors, Hedgehog morphogens and olfactory cues) and concentrates their downstream signaling machinery to send specific molecular responses back into the cell. Despite these fascinating properties, the cilium has historically been the least studied cellular organelle and most of the fundamental questions concerning cilium biogenesis and function remain unanswered. Nowhere is our knowledge gap more striking than for the ciliopathies, a class of inherited disorders of the cilium whose central features include obesity, kidney malformations and retinal degeneration. We thus intend to uncover the molecular machines that build cilia and convey information into and out of cilia by applying proteomics, cellular imaging and in vitro reconstitution assays to entry points provided by human genetics.
Trafficking of signaling receptors to the primary cilium
In 2007, we discovered the BBSome, an octameric protein complex defective in the ciliopathy Bardet-Biedl Syndrome (BBS). Since then, we have shown that a key task of the BBSome is to sort signaling receptors to cilia and we have reconstituted the molecular activity of the BBSome from pure components to demonstrate that the BBSome functions as a vesicular sorting machine akin to clathrin, COPI and COPII coats. Our first aim is now to apply structural, biochemical and biophysical tools in search of at an atomic-level understanding of the molecular work produced by the BBSome. Secondly, the BBSome coat model suggests that the variety of symptoms found in BBS patients (including obesity) results from the failure to transport signaling receptors to the cilium. It is therefore critical that we biochemically isolate the signaling receptors associated with the BBSome in order to identify specific ciliary signaling factors involved in body weight homeostasis.
Functional roles of the tubulin code
Since its discovery more than 25 years ago, the acetylation of alpha-tubulin has remained the marker of choice for cilia and other stable microtubule structures. Yet, the functional consequence of tubulin acetylation has remained enigmatic in large part because the specific enzyme responsible for this key modification has escaped detection. We have now discovered the major tubulin acetyltransferase and showed that tubulin acetylation plays a critical role in ciliogenesis, in cell migration and in mechanosensation. Surprisingly, acetylation takes place inside the lumen of microtubules, the dark side of microtubules that most researchers had considered to be inaccessible to intruding proteins. Thus, the identification of factors that read the acetylation mark promises to uncover a whole new facet of microtubule complexity, while the generation of organisms lacking tubulin acetylation will reveal novel functions of stable microtubules conserved throughout evolution.