Abstract
Bardet-Biedl syndrome is a model ciliopathy. Although the characterization of BBS proteins has evidenced their involvement in cilia, extraciliary functions for some of these proteins are also being recognized. Importantly, understanding both cilia and cilia-independent functions of the BBS proteins is key to fully dissect the cellular basis of the syndrome. Here we characterize a functional interaction between BBS4 and the secreted protein FSTL1, a protein linked to adipogenesis and inflammation among other functions. We show that BBS4 and cilia regulate FSTL1 mRNA levels, but BBS4 also modulates FSTL1 secretion. Moreover, we show that FSTL1 is a novel regulator of ciliogenesis thus underscoring a regulatory loop between FSTL1 and cilia. Finally, our data indicate that BBS4, cilia and FSTL1 are coordinated during the differentiation of 3T3-L1 cells and that FSTL1 plays a role in this process, at least in part, by modulating ciliogenesis. Therefore, our findings are relevant to fully understand the development of BBS-associated phenotypes such as obesity.
Highlights
The ciliopathies are a group of human genetic diseases characterized by an overlapping set of phenotypes including cystic kidney disease, retinal degeneration, central nervous defects, polydactyly, diabetes and obesity
BBS4 contains a series of tetratricopeptide repeats (TPRs) arranged in tandem, a motif typically involved in mediating protein-protein interactions[39, 40], and is incorporated into the BBSome at the end of the assembly process[18]
We evaluated the levels of follistatin-like 1 (FSTL1) 48 hours after BBS4 knockdown (KD) observing a significant decrease in FSTL1 abundance, both intracellular and secreted (Fig. 1A and C)
Summary
The ciliopathies are a group of human genetic diseases characterized by an overlapping set of phenotypes including cystic kidney disease, retinal degeneration, central nervous defects, polydactyly, diabetes and obesity This group of disorders presents a common cellular defect: problems in the formation, maintenance and/or function of primary cilia[1,2,3]. The BBS proteins have been shown to participate in the regulation of cilia/basal body-associated signaling pathways such as Wnt and Shh[20,21,22]. While cilia dysfunction results in a reduction in FSTL1 mRNA levels, knockdown of BBS4 affects both FSTL1 mRNA and the secretion of the protein. Our data indicate that BBS4, FSTL1 and the cilium are co-regulated during the differentiation of 3T3-L1 pre-adipocytes, and this process can be affected by modulating the levels of FSTL1. We report a novel function for FSTL1 in the regulation of ciliogenesis and demonstrate a role for FSTL1 in modulating the differentiation of 3T3-L1 cells
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