Agborbesong, Ewud

Abstract Ciliopathies are a group of human diseases that affect the cellular cilia or the cilia anchoring structures, the bosal bodies, or ciliary function. Macrophage migration inhibitory factor (MIF) as an important inflammatory cytokine plays a prominent role in the pathogenesis of various human diseases. However, the role of MIF in ciliopathies remains elusive. In this study, we show that MIF is a structure protein of basal bodies, which forms a ring-like structure at proximal end of centrioles to regulate cilia assembly and elongation. Importantly, we identify MIF as a novel transcriptional factor, which regulates the expression of ciliary genes and genes associated with different signaling pathways. The phosphatidylinositol-5-phosphate 4-kinase type 2 alpha (PIP4K2a) mediated MIF phosphorylation at S91 is necessary for the nuclear translocation of MIF, a process that is regulated by 14-3-3ζ. This study suggests that MIF is a key player in cilia biogenesis and transcriptional regulation in homeostasis.

Hereditary renal cystic diseases are characterized by defects in primary cilia of renal tubular epithelial cells and abnormality of tubular epithelium, which ultimately result in the development of renal cysts. However, the mechanism leading from abnormality of the tubular epithelium to cystogenesis is not well understood. In this report, we demonstrate a critical role for Robo2 in regulating epithelial development, including ciliogenesis, polarization, and differentiation. We found that Robo2 deficiency results in cystic kidneys, and the cyst cells showed defective cilia and polarity defects in tubular epithelium. The cyst cells, less than terminally differentiated, continue to proliferate. We further established that Robo2 works with p53 as well as polarity and ciliary proteins (Par3, PKCς, ZO-2, and Claudin-2) to regulate these processes. Robo2 binds to Baiap2 (also known as IRSp53) through the IRSp53/MIM homology domain in renal epithelial cells. This binding allows Robo2 to phosphorylate MDM2 at Ser166 via Baiap2 and maintain p53 homeostasis. Disruption of the Robo2-Baiap2 complex causes MDM2 to be subjected to dephosphorylation, leading to a high level of active p53, and initiated p53-mediated cellular senescence via p21 and decreased the expression of ZO-1, ZO-2, PKCς, Par3, and Claudin-2 proteins, resulting in defects in epithelial development, including ciliogenesis, polarization, and differentiation. Importantly, double knockout of Robo2 and p53 rescued all the epithelial defects in kidneys compared with those in Robo2 -knockout kidneys. Taken together, the present results demonstrate that Robo2 deficiency causes renal cystic disease, which is largely dependent on defective Robo2-Baiap2 integrated signaling in kidneys.