Kennedy et al. identify a mutation in coiled-coil domain containing protein 88b (Ccdc88b) that confers protection against lethal neuroinflammation during experimental cerebral malaria. CCDC88B is expressed in immune cells and regulates T cell maturation and effector functions. In humans, the CCDC88B gene maps to a locus associated with susceptibility to several inflammatory and autoimmune disorders.

The limited regenerative capacity of the glomerular podocyte following injury underlies the development of glomerulosclerosis and progressive renal failure in a diverse range of kidney diseases. We discovered that, in the kidney, cyclin I is uniquely expressed in the glomerular podocyte, and have constructed cyclin I knock-out mice to explore the biological function of cyclin I in these cells. Cyclin I knock-out (؊/؊) podocytes showed an increased susceptibility to apoptosis both in vitro and in vivo. Following induction of experimental glomerulonephritis, podocyte apoptosis was increased 4-fold in the cyclin I ؊/؊ mice, which was associated with dramatically decreased renal function. Our previous data showed that the Cdk inhibitor p21Cip1/Waf1 protects podocytes from certain apoptotic stimuli. In cultured cyclin I ؊/؊ podocytes, the level of p21Cip1/Waf1 was lower at base line, had a shorter half-life, and declined more rapidly in response to apoptotic stimuli than in wild-type cells. Enforced expression of p21Cip1/Waf1 reversed the susceptibility of cyclin I ؊/؊ podocytes to apoptosis. Cyclin I protects podocytes from apoptosis, and we provide preliminary data to suggest that this is mediated by stabilization of p21 Cip1/Waf1 .Cyclins were originally discovered for their role in governing cell cycle progression and proliferation (1). More recently it has been appreciated that cyclins may influence a wide range of additional cellular functions, including apoptosis, hypertrophy, and differentiation. The increasingly diverse members of the cyclin protein family are all characterized by the presence of a conserved domain through which they bind to cyclin-dependent kinases, the cyclin box (2). Cyclin I, the focus of this manuscript, is most abundant in post-mitotic tissues. In contrast to the classical cyclins, its level does not fluctuate during the cell cycle (3, 4). Cyclin I shows highest sequence homology to cyclins G1 and G2, and these three proteins are considered to form a separate subgroup (5). However, the biological function of cyclin I is not known.Our data show that within the kidney cyclin I is specifically expressed by glomerular podocytes. These are terminally differentiated, post-mitotic, highly specialized epithelial cells, which serve as the major barrier to prevent the excretion of serum proteins into the urine. The inability to replace podocytes lost by apoptosis is thought to underlie the subsequent development of glomerulosclerosis and progressive renal impairment, regardless of the initiating injury (6 -14). Given their limited regenerative capacity, prevention of podocyte apoptosis is of critical importance for the maintenance of normal renal function.The restricted expression of cyclin I to the renal podocyte suggested that it might play a specialized biological role in these cells. We describe here the characterization of cyclin I expression in the normal kidney and the first analysis of its function using cyclin I knock-out mice. We report that cyclin I regulates podocyte apoptosis, both ...

The Coiled Coil Domain Containing Protein 88B (CCDC88B) gene is associated with susceptibility to several inflammatory diseases in humans and its inactivation in mice protects against acute neuroinflammation and models of intestinal colitis. We report that mice lacking functional CCDC88B (Ccdc88b Mut) are defective in several dendritic cells (DCs)-dependent inflammatory and immune reactions in vivo. In these mice, an inflammatory stimulus (LPS) fails to induce the recruitment of DCs into the draining lymph nodes (LNs). In addition, OVA-pulsed Ccdc88b Mut DCs injected in the footpad do not induce recruitment and activation of antigen-specific CD4 + and CD8 + T cells in their draining LN. Experiments in vitro indicate that this defect is independent of the ability of mutant DCs to capture and present peptide antigen to T cells. Rather, kinetic analyses in vivo of wild-type and Ccdc88b Mut DCs indicate a reduced migration capacity in the absence of the CCDC88B protein expression. Moreover, using time-lapse light microscopy imaging, we show that Ccdc88b Mut DCs have an intrinsic motility defect. Furthermore, in vivo studies reveal that these reduced migratory properties lead to dampened contact hypersensitivity reactions in Ccdc88b mutant mice. These findings establish a critical role of CCDC88B in regulating movement and migration of DCs. Thus, regulatory variants impacting Ccdc88b expression in myeloid cells may cause variable degrees of DC-dependent inflammatory response in situ, providing a rationale for the genetic association of CCDC88B with several inflammatory and autoimmune diseases in humans.