Signal transduction is a key process through which a cell receives signals from the environment and relays them. It has recently been discovered that many signal transduction pathways utilize the primary cilium as a """"""""signaling antenna."""""""" Proper ciliary localization of receptors and downstream effectors is required for activation of fundamental signaling pathways such as the Hedgehog pathway. Therefore, it is essential to understand how transmembrane signaling molecules such as receptors are correctly targeted to the ciliary membrane rather than the adjoining plasma membrane or other cellular compartments. While trafficking through other parts of the secretory system has been well studied, little is known about how proteins are sorted to the cilium and delivered there. A number of multi-system diseases, such as Bardet-Biedl syndrome (BBS), are thought to result from altered ciliary signaling, implying that primary cilia are required in most organ systems. This proposal will focus on one facet of BBS, obesity. Several lines of evidence suggest that obesity in BBS patients is caused by mislocalization of signaling receptors, such as the leptin receptor, in the absence of a functional BBSome (complex of BBS proteins). This study will examine the interaction of the leptin receptor with the BBSome using physiologically relevant cell biological studies in hippocampal and hypothalamic neurons. The region of the leptin receptor responsible for its ciliary targeting will be mapped. The role of the BBSome in potentiating signaling downstream of the leptin receptor will also be examined. In addition, structural biology, including cryo-electron microscopy and X-ray crystallography, will be used to determine the molecular mechanism by which the BBSome transports signaling receptors to or within the cilium. By learning how obesity occurs in BBS, we may discover new therapeutic targets that will allow for new treatments for obesity. Indeed, the BBSome itself is an attractive therapeutic target, so ascertaining its structure will provide the molecular detail that is required for designing pharmacologic interventions. Childhood obesity is a critical public health issue that we will address by studying an inherited form of obesity, Bardet-Biedl syndrome (BBS). In this project, we will examine how a stable particle of BBS proteins transports body weight sensors to the cellular antenna. Understanding how body weight is regulated may lead to new therapies for obesity.
| Jin, Hua; White, Susan Roehl; Shida, Toshinobu et al. (2010) The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell 141:1208-19 |
