My laboratory studies the protein network that builds and maintains the primary cilium and the pathophysiological mechanisms of cilia-related diseases. The primary cilium is a sensory organelle present in most cells in vertebrates and transduces extracellular signals into the cell body. Due to its ubiquitous presence, ciliary dysfunction is associated with multiple developmental defects and disorders including blindness (photoreceptor degeneration), cystic kidney, neural tube patterning defects, and obesity. Accordingly, humans with ciliary defects often present syndromic diseases with multiple phenotypic components. We investigate the protein composition of the ciliary protein network, what the roles of these proteins are, how loss of these proteins results in each phenotypic component of the cilia-related diseases, and how to prevent or treat the disease.

Bardet-Biedl syndrome (BBS) is one of the syndromic, hereditary diseases associated with ciliary dysfunction. To date, seventeen BBS genes (BBS1 - BBS17) have been identified and mutations in these genes commonly cause a group of phenotypes such as photoreceptor degeneration, obesity, polydactyly (extra digits in hands and feet), cognitive impairment, kidney anomalies, and diabetes. Among the known BBS proteins, seven (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8 and BBS9) form a stable complex, the BBSome, that mediates protein trafficking to the ciliary membrane. BBS3 (also known as ARL6) is a small GTPase that regulates ciliary trafficking of the BBSome. We have determined that three BBS proteins (BBS6, BBS10, and BBS12) form another complex with the CCT family of group II chaperonins (the BBS/CCT chaperonin complex) and this complex mediates BBSome assembly. We also identified LZTFL1 as a BBSome interacting protein and determined that LZTFL1 negatively regulates the ciliary trafficking activity of the BBSome. Recently, mutations in LZTFL1 were found in human BBS patients, and have generated an Lztfl1 knock-out mouse line with which we are currently investigating the roles of Lztfl1 in vivo.

We are also interested in ciliary trafficking mechanisms of other ciliopathy proteins that cause photoreceptor degeneration. The photoreceptor outer segment (OS) is a highly specialized primary cilium, sharing many key components and regulatory mechanisms with primary cilia. Not surprisingly, mutations that affect primary cilia structure or function also disrupt the OS and cause photoreceptor degeneration. We have recently determined the protein-protein interaction network of INPP5E, a ciliopathy protein that causes Joubert syndrome (JBTS) when mutated, and its ciliary targeting mechanism. Using cell biological, biochemical, and proteomics approaches, we determined that INPP5E is targeted to primary cilia by sequential interactions with PDE6D, CEP164, and ARL13B. Mutations in these genes also cause ciliopathies. Other proteins identified in this study are great candidates for currently unknown ciliopathy genes.

We will continue our effort to elucidate the mechanisms of ciliary trafficking and the molecular etiology of cilia-related diseases so that more advanced therapies can be developed.