Background: Mutations 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. Methods: We 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. Results: Here 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. Conclusion: This 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 with NUP205 mutations. Moreover, this study suggests an important role of YAP/TAZ signaling in human FSGS.
Mutations in genes encoding nuclear pore proteins (NUPs) lead to the development of steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis (FSGS). However, the precise molecular mechanisms by which NUP dysfunction contributes to podocyte injury preceding FSGS remain unclear. The tightly regulated activity of Yes-associated protein (YAP) and WW-domain-containing transcription regulator 1 (TAZ), the transcriptional effectors of the Hippo pathway, is crucial for podocytes and the maintenance of the glomerular filter. In this study, we investigate the impact of NUPs on the regulation of YAP/TAZ nuclear import and activity in podocytes. In unbiased interactome studies using quantitative label-free mass spectrometry, we identify the FSGS disease gene products NUP107, NUP133, NUP205, and Exportin-5 (XPO5) as components of YAP and TAZ protein complexes in podocytes. Moreover, we demonstrate that NUP205 is essential for YAP/TAZ nuclear import. Consistently, both the nuclear interaction of YAP/TAZ with TEA domain transcription factor 1 and their transcriptional activity were dependent on NUP205 expression. Additionally, we elucidate a regulatory feedback mechanism whereby YAP activity is modulated in response to TAZ-mediated NUP205 expression. In conclusion, this study establishes a connection between the FSGS disease protein NUP205 and the activity of the transcriptional regulators and Hippo effectors YAP and TAZ and it proposes a potential pathological role of YAP/TAZ dysregulation in podocytes of patients with pathogenic NUP205 variants.
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