ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 25 S5.4

The molecular pathophysiology of the human obesity disorder, Bardet Biedl syndrome (BBS)

Val Sheffield

Department of Pediatrics and Howard Hughes Medical Institute, University of Iowa, Iowa, USA.

Bardet-Biedl syndrome (BBS) is a heterogeneous autosomal recessive disorder characterized by obesity, retinopathy, cognitive abnormalities, and polydactyly and other congenital anomalies. Patients also have an increased incidence of hypertension and diabetes. Mutations in at least 14 genes have been reported to independently cause BBS. In order to better understand the pathophysiology of BBS, we have generated BBS mouse models and have investigated the interaction of the protein products of the BBS genes. Seven BBS proteins form a stable protein complex known as the BBSome, which promotes ciliary membrane elongation through Rab8. In addition, we have shown that a component of the BBSome (BBS1) interacts directly with the leptin receptor. Three additional BBS proteins have chaperonin homology and play a role in BBSome formation. BBS3, an ADP-ribosylation factor (ARF)-like small GTPase also known as ARL6, is not part of the BBSome complex and does not have chaperonin homology. We used Bbs3−/− mice to determine whether Bbs3 is required for BBSome formation. Loss of Bbs3 does not affect BBSome protein levels or BBSome formation. However, both the BBSome and Bbs3 localize to cilia, and loss of Bbs3 disrupts localization of BBSome proteins to cilia. Conversely, the BBSome is required for ciliary localization of BBS3.

Many signaling proteins including G protein-coupled receptors localize to primary cilia, regulating cellular processes including differentiation, proliferation, organogenesis, and tumorigenesis. Bardet-Biedl syndrome (BBS) proteins are involved in maintaining ciliary function by mediating protein trafficking to the cilia.

The mechanisms governing ciliary trafficking by BBS proteins are not well understood. We show that a novel protein, Leucine-zipper transcription factor-like 1 (LZTFL1), interacts with the BBSome, and regulates ciliary trafficking of this complex. We also show that all BBSome subunits are required for BBSome ciliary entry and that reduction of LZTFL1 restores BBSome ciliary trafficking in BBS3 and BBS5 depleted cells. Our findings indicate that LZTFL1 is an important regulator of BBSome ciliary trafficking, and as such is a target for treatment.

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