Depletion of BBSome Subunits Alters Receptor Endocytosis and Promotes EMT via TGF-β Signaling

Summary Ciliopathies are genetic disorders caused by defects in the structure or function of the cilia and their related structures. Bardet-Biedl syndrome (BBS) is a complex ciliopathy with varied symptoms, probably due to altered membrane receptor signalling pathways. This study explores the role of BBS1 and BBS4 gene deficiencies in receptor trafficking and epithelial-mesenchymal transition (EMT) in retinal epithelial cells. Deficiencies in these genes, key components of the BBSome complex, led to shorter cilia and disrupted receptor endocytosis. BBS1 knockout (KO) cells showed delayed transferrin internalisation and increased recycling of TGFBR1, promoting EMT. On the contrary, BBS4 KO cells had higher receptor degradation but no affected recycling. These disruptions suggest that BBSome regulates both ciliary and nonciliary pathways. Increased EMT markers in BBS1 KO cells were associated with higher cell migration and reduced proliferation, highlighting the role in receptor trafficking and potential therapeutic targets for retinal degeneration in BBS. Highlights Depletion of BBS1 and BBS4 alters endocytic trafficking as well as length and/or frequency of primary cilia, affecting the internalisation of receptors at the ciliary pocket. BBS1 knockout cells show increased EMT, up-regulation of mesenchymal markers, enhanced migration, and reduced proliferation after TGF-β stimulation. BBS1 knockout cells exhibit increased TGFBR1 recycling, while BBS4 KO cells exhibit balanced receptor degradation and recycling, indicating distinct roles of these two BBSome components in receptor trafficking. Targeting the TGF-β pathway and EMT may provide therapeutic options for retinal degeneration in Bardet-Biedl syndrome. Competing Interest Statement The authors have declared no competing interest.