Protein trafficking to primary cilia and disease mechanisms of human ciliopathies

Our research is focused on elucidating the protein network that builds and maintains the primary cilium and determining disease mechanisms of human ciliopathies, a group of human genetic diseases associated with ciliary defects. The primary cilium is a sensory organelle present in most cells in vertebrates and transduces various extracellular signals into the cell body. Due to its ubiquitous existence and involvement in multiple signaling pathways, mutations that cause deficiencies in ciliary structure and/or function lead to multiple developmental defects and disorders including photoreceptor degeneration, kidney cyst, neural tube and limb patterning defect, and obesity. We investigate the ciliary protein interaction network that builds the primary cilium, roles of each protein in this network, how loss of these proteins results in each phenotypic component of ciliopathies, and how to prevent or treat the disease.

Bardet-Biedl syndrome (BBS) is one of the ciliopathies with phenotypic features such as photoreceptor degeneration, obesity, polydactyly (extra digits in hands and feet), cognitive impairment, kidney anomalies, and diabetes. Among the BBS genes identified so far, seven (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8 and BBS9) form a stable complex, the BBSome, that mediates protein trafficking to the ciliary membrane. 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 mediate BBSome assembly. We also identified LZTFL1 as a BBSome interacting protein and determined that LZTFL1 regulates BBSome ciliary trafficking activity. We are currently investigating roles of Lztfl1 in vivo using an Lztfl1 mutant mouse line and how loss of BBS proteins results in photoreceptor degeneration.

While BBS proteins constitute one mechanism of ciliary trafficking, many ciliary proteins are transported by BBSome-independent mechanisms. We are also interested in these BBSome-independent, ciliary trafficking mechanisms. For example, we have recently determined how INPP5E, a ciliopathy protein that causes Joubert syndrome (JBTS) when mutated, is targeted to cilia. We will continue our effort to discover mechanisms by which the primary cilium is constructed and the molecular etiology of cilia-related diseases such that more advanced, mechanism-based therapies can be developed.

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Department/Program Affiliations:
Molecular Medicine
Ophthalmology and Visual Sciences