The FSGS disease gene product and nuclear pore protein NUP205 regulates nuclear localization and activity of the transcriptional regulators YAP and TAZ in podocytes

Abstract

ABSTRACTBackgroundMutations in genes encoding nuclear pore proteins (NUPs) cause steroid-resistant nephrotic syndrome (SRNS) and focal and segmental glomerulosclerosis (FSGS). The mechanisms of how NUP deficiency may cause podocyte dysfunction and failure of the kidney filtration barrier are elusive. The tightly controlled activity of the transcriptional effectors of the evolutionarily conserved Hippo pathway YAP and TAZ is essential for podocyte homeostasis. Here we analyze the role of NUPs in controlling YAP/TAZ nuclear import and activity in podocytes.MethodsWe used quantitative label-free mass spectrometry to characterize the YAP/TAZ interactomes in podocytes, particularly identifying NUP interactions. Moreover, we specifically studied NUP205 in controlling YAP/TAZ nuclear import and YAP/TAZ-dependent target gene expression.ResultsHere we identify the disease-causing nuclear pore proteins NUP107, NUP133, NUP205, and XPO5 as components of YAP and TAZ protein complexes in podocytes. We demonstrate that NUP205 is essential for YAP/TAZ nuclear import. The nuclear interaction of YAP/TAZ with TEAD1 and their transcriptional activity were dependent on NUP205 expression. Furthermore, we identify a feedback regulatory mechanism that controls YAP activity depending on TAZ-mediated NUP205 expression.ConclusionThis study links the disease protein NUP205 with the activity of the transcriptional regulators and Hippo effectors YAP and TAZ and suggests a pathogenic role of YAP/TAZ-deregulation in podocytes in patients withNUP205mutations. Moreover, this study suggests an important role of YAP/TAZ signaling in human FSGS.SIGNIFICANCE STATEMENTUnderstanding the interference of signaling pathways in genetic diseases is essential to finally develop tailored treatment strategies. The increasing number of pathogenic variants causing focal-segmental glomerulosclerosis (FSGS) comprises genes encoding for proteins of the nuclear-cytoplamic shuttling machinery. We here found several of these proteins in an unbiased interactome analysis of the Hippo signaling effector proteins YAP and TAZ in podocytes, pointing to a connection between nucleoporins and the Hippo pathway. Further analyses confirmed that NUP205 is essential for correct YAP/TAZ shuttling; depletion of NUP205 resulted in cytoplasmic retention and inactivation of YAP/TAZ. We suggest the nuclear pore and hippo signaling as a pathogenic module in FSGS.