NEK8, a NIMA-family protein kinase at the core of the ciliary INV complex

Here we describe the current knowledge about the ciliary kinase NEK8, highlighting what we know and what we don't know about its regulation, substrates and potential functions. We also review the literature about the pathological consequences of different NEK8 variants in patients of nephronophthisis, renal-hepatic-pancreatic dysplasia and autosomal dominant polycystic kidney disease, three different types of ciliopathies. NEK8 belongs to the NIMA family of serine/threonine protein kinases. Like its closest relative, NEK9, it contains a protein kinase and an RCC1 domain, but lacks the C-terminal region that is key for NEK9's regulation as a G2/M kinase. Importantly, NEK8 localizes to cilia as part of a multimeric protein complex that assembles in a fibrillar fashion at the proximal half of this signaling organelle, defining what is known as the INV compartment. NEK8 and its INV compartment partners inversin, ANKS6 and NPHP3 are necessary for left-right determination and the correct development of different organs such as the kidney, the heart and the liver. But the kinase substrates, regulatory mechanism and activating cues and thus the molecular basis of NEK8 important physiological roles remain elusive. We present the current findings regarding NEK8 and also highlight what we miss in order to progress towards the understanding of the kinase and the function of the INV complex at the cilia.