The ciliopathy disease protein NPHP9 promotes nuclear delivery and activation of the oncogenic transcriptional regulator TAZ

Abstract

Nephronophthisis (NPH) is a genetically heterogenous kidney disease and represents the most common genetic cause for end-stage renal disease in children. It is caused by the mutation of genes encoding for the nephrocystin proteins (NPHPs) which localize to primary cilia or centrosomes, classifying this disease as a 'ciliopathy'. Recently, it has been shown that NPHP4 acts as a potent negative regulator of mammalian Hippo signalling by interacting with the Lats protein kinase and controlling the phosphorylation of the oncogenic transcriptional activator TAZ. Here, we demonstrate that NPHP9, another NPH family member, also controls TAZ activity by a distinct mechanism. NPHP9, which is also called NEK8, directly interacted with TAZ and induced nuclear translocation of the TAZ/NPHP9 protein complex. Binding of NPHP9 to TAZ was enhanced in a TAZ mutant that lost its ability to bind 14-3-3, suggesting that 14-3-3 and NPHP9 may compete for TAZ binding, with 14-3-3 favouring cytoplasmic retention and NPHP9 mediating nuclear delivery. Consistently, co-expression of NPHP4, which inhibits TAZ phosphorylation at the 14-3-3 binding site through the inhibition of Lats kinase activity, induced efficient nuclear delivery of the TAZ/NPHP9 protein pair. Consistent with a role for TAZ in controlling proliferation and tumorigenesis, the downregulation of NPHP9 inhibited the TAZ-dependent proliferation of hippo-responsive normal epithelial and also breast cancer cells. As NPHP9 has been shown to be upregulated in breast cancer, these data do not only support a critical role for TAZ/hippo signalling in the pathogenesis of NPH but may also imply a possible role for NPHP9 in TAZ-mediated tumorigenesis.

YAP and TAZ: a nexus for Hippo signaling and beyond

“…Members of the nephrocystin (NPHP) family, established primary cilia-associated proteins [159], induce TAZ (and YAP) activity. NPHP4 binds to LATS and negatively regulates LATS activity, whereas NPHP3 and NPHP9 bind directly to TAZ and potentially compete with 14-3-3 binding to relieve cytoplasmic retention [160,161]. Therefore, members of the NPHP family increase transcriptional activity of YAP and TAZ [153].…”

Nuclear roles for cilia-associated proteins

“…For example, NPHP4 (nephrocystin-2: OMIM 607215) interacts with and inhibits the LATS1 kinase, leading to the nuclear accumulation of the transcriptional co-activators YAP and TAZ, two proteins involved in the HIPPO (hypoxia) signaling system [33]. NPHP9 (also known as NEK8–OMIM 609799) has been found to interact with TAZ, leading to the nuclear localization of the NPHP9–TAXZ complex [34]. TAZ is normally exported to the cytoplasm through interactions with 14-3-3 proteins; NPHP9 appears to compete with 14-3-3 proteins for TAZ binding.…”

Actin remodelling factors control ciliogenesis by regulating YAP/TAZ activity and vesicle trafficking

“…Recent studies have shown that the ciliopathy proteins NPHP4 and NPHP9 negatively regulate the Hippo pathway and promote nuclear targeting of TAZ 22,23 . In addition, the Hippo pathway component MST1/2-SAV complex was identified as a regulator of a cilium disassembly pathway involving AURKA and HDAC6 (ref.…”