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The Bardet-Biedl syndrome protein complex regulates cell migration and tissue repair through a Cullin-3/RhoA pathway
Journal article   Open access   Peer reviewed

The Bardet-Biedl syndrome protein complex regulates cell migration and tissue repair through a Cullin-3/RhoA pathway

Deng-Fu Guo and Kamal Rahmouni
American Journal of Physiology: Cell Physiology, Vol.317(3), pp.C457-C465
09/01/2019
DOI: 10.1152/ajpcell.00498.2018
PMCID: PMC6766617
PMID: 31216194
url
https://doi.org/10.1152/ajpcell.00498.2018View
Published (Version of record) Open Access

Abstract

Cell motility and migration play critical roles in various physiological processes and disease states. Here, we show that the BBBsome, a macromolecule composed of eight Bardet-Biedl syndrome (BBS) proteins including BBS1, is a critical determinant of cell migration and wound healing. Fibroblast cells derived from mice or humans harboring a homozygous missense mutation (BBS1\n) that disrupt the BBSome exhibit defects in migration and wound healing. Furthermore, we demonstrate that BBS1\nmice have significantly delayed wound closure. In line with this, we provide data suggesting that BBS1\nfibroblasts have impaired platelet-derived growth factor-AA (PDGF) receptor-α signaling, a key regulator of directional cell migration acting as a chemoattractant during postnatal migration responses such as wound healing. In addition, we show that BBS1\nfibroblasts have upregulated RhoA expression and activity. The relevance of RhoA upregulation is demonstrated by the ability of RhoA-kinase inhibitor Y27632 to partially rescue the migration defect of BBS1\nfibroblasts cells. We also show that accumulation of RhoA protein in BBS1\nfibroblasts cells is associated with reduction and inactivation of the ubiquitin ligase Cullin-3. Consistent with this, Cullin-3 inhibition with MLN4924 is sufficient to reduce migration of normal fibroblasts. These data implicate the BBSome in cell motility and tissue repair through a mechanism that involves PDGF receptor signaling and Cullin-3-mediated control of RhoA.
 Cullin Proteins - antagonists & inhibitors Humans Mice, Inbred C57BL Cells, Cultured Enzyme Inhibitors - pharmacology Male Mice, Transgenic rhoA GTP-Binding Protein - antagonists & inhibitors Cullin Proteins - physiology rhoA GTP-Binding Protein - physiology Cyclopentanes - pharmacology Pyrimidines - pharmacology Cell Movement - physiology Microtubule-Associated Proteins - physiology Cell Movement - drug effects Animals Bardet-Biedl Syndrome - genetics Female Signal Transduction - physiology Mice Gene Knock-In Techniques - methods

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