The nephronophthisis gene product NPHP2/Inversin interacts with Aurora A and interferes with HDAC6-mediated cilia disassembly

Abstract

Nephronophthisis (NPH) is a rare recessive disease caused by several different gene mutations. Most gene products localize to the cilium, and thus, the various NPH manifestations including kidney cysts and situs inversus have been linked to ciliary defects. Here, we describe that targeted knockdown of NPHP2 significantly reduced the number of cilia on polarized MDCK cells. As one of the underlying molecular mechanisms, we identified a direct interaction between NPHP2 and Aurora A, a cell cycle kinase that promotes ciliary disassembly after activation by Hef1. NPHP2 inhibited the phosphorylation and activation of Aurora A, and reduced its kinase activity in vitro. Aurora A and histone deacetylase inhibitors ameliorated the ciliogenesis defect in NPHP2-deficient MDCK cells, supporting our hypothesis that NPHP2 is involved in the control of ciliary disassembly. Furthermore, we observed that nephrocystin (NPHP1), an interaction partner of NPHP2, also binds Aurora A, exerting very similar inhibitory effects on Hef1-mediated Aurora A activation. Taken together, these findings suggest that NPHP gene products can interfere with ciliary disassembly through interaction with the Hef1/Aurora A module, thereby modulating cell cycle control and cell proliferation.