Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer.

BACKGROUND: CDC37 is a key determinant of client kinase recruitment to the HSP90 chaperoning system. We hypothesized that kinase-specific dependency on CDC37 alters the efficacy of targeted therapies for metastatic colorectal cancer (mCRC). MATERIAL AND METHODS: Two independent mCRC cohorts were analyzed to compare the survival outcomes between CDC37-high and CDC37-low patients (stratified by the median cutoff values): the CALGB/SWOG 80405 trial (226 and 207 patients receiving first-line bevacizumab- and cetuximab-containing chemotherapies, respectively) and Japanese retrospective (50 refractory patients receiving regorafenib) cohorts. A dataset of specimens submitted to a commercial CLIA-certified laboratory was utilized to characterize molecular profiles of CDC37-high (top quartile, N = 5055) and CDC37-low (bottom quartile, N = 5055) CRCs. RESULTS: In the bevacizumab-treated group, CDC37-high patients showed significantly better progression-free survival (PFS) (median 13.3 vs 9.6 months, hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44-0.79, p < 0.01) than CDC37-low patients. In the cetuximab-treated group, CDC37-high and CDC37-low patients had similar outcomes. In the regorafenib-treated group, CDC37-high patients showed significantly better overall survival (median 11.3 vs 6.0 months, HR 0.24, 95% CI 0.11-0.54, p < 0.01) and PFS (median 3.5 vs 1.9 months, HR 0.51, 95% CI 0.28-0.94, p = 0.03). Comprehensive molecular profiling revealed that CDC37-high CRCs were associated with higher VEGFA, FLT1, and KDR expressions and activated hypoxia signature. CONCLUSIONS: CDC37-high mCRC patients derived more benefit from anti-VEGF therapies, including bevacizumab and regorafenib, but not from cetuximab. Molecular profiles suggested that such tumors were dependent on angiogenesis-relating pathways.

Mycobacterial chaperonins in cellular proteostasis: Evidence for chaperone function of Cpn60.1 and Cpn60.2-mediated protein folding.

Mycobacterium tuberculosis encodes two chaperonin proteins, MtbCpn60.1 and MtbCpn60.2, that share substantial sequence similarity with the Escherichia coli chaperonin, GroEL. However, unlike GroEL, MtbCpn60.1 and MtbCpn60.2 purify as lower-order oligomers. Previous studies have shown that MtbCpn60.2 can functionally replace GroEL in E. coli, while the function of MtbCpn60.1 remained an enigma. Here, we demonstrate the molecular chaperone function of MtbCpn60.1 and MtbCpn60.2, by probing their ability to assist the folding of obligate chaperonin clients, DapA, FtsE and MetK, in an E. coli strain depleted of endogenous GroEL. We show that both MtbCpn60.1 and MtbCpn60.2 support cell survival and cell division by assisting the folding of DapA and FtsE, but only MtbCpn60.2 completely rescues GroEL-depleted E. coli cells. We also show that, unlike MtbCpn60.2, MtbCpn60.1 has limited ability to support cell growth and proliferation and assist the folding of MetK. Our findings suggest that the client pools of GroEL and MtbCpn60.2 overlap substantially, while MtbCpn60.1 folds only a small subset of GroEL clients. We conclude that the differences between MtbCpn60.1 and MtbCpn60.2 may be a consequence of their intrinsic sequence features, which affect their thermostability, efficiency, clientomes and modes of action.

Structural and Dynamic Disturbances Revealed by Molecular Dynamics Simulations Predict the Impact on Function of CCT5 Chaperonin Mutations Associated with Rare Severe Distal Neuropathies.

Mutations in genes encoding molecular chaperones, for instance the genes encoding the subunits of the chaperonin CCT (chaperonin containing TCP-1, also known as TRiC), are associated with rare neurodegenerative disorders. Using a classical molecular dynamics approach, we investigated the occurrence of conformational changes and differences in physicochemical properties of the CCT5 mutations His147Arg and Leu224Val associated with a sensory and a motor distal neuropathy, respectively. The apical domain of both variants was substantially but differently affected by the mutations, although these were in other domains. The distribution of hydrogen bonds and electrostatic potentials on the surface of the mutant subunits differed from the wild-type molecule. Structural and dynamic analyses, together with our previous experimental data, suggest that genetic mutations may cause different changes in the protein-binding capacity of CCT5 variants, presumably within both hetero- and/or homo-oligomeric complexes. Further investigations are necessary to elucidate the molecular pathogenic pathways of the two variants that produce the two distinct phenotypes. The data and clinical observations by us and others indicate that CCT chaperonopathies are more frequent than currently believed and should be investigated in patients with neuropathies.

A genome-wide CRISPR screen identifies the CCT chaperonin as a critical regulator of vesicle trafficking.

Vesicle trafficking is a fundamental cellular process that controls the transport of various proteins and cargos between cellular compartments in eukaryotes. Using a combination of genome-wide CRISPR screening in mammalian cells and RNAi screening in Caenorhabditis elegans, we identify chaperonin containing TCP-1 subunit 4 (CCT4) as a critical regulator of protein secretion and vesicle trafficking. In C. elegans, deficiency of cct-4 as well as other CCT subunits impairs the trafficking of endocytic markers in intestinal cells, and this defect resembles that of dyn-1 RNAi worms. Consistent with these findings, the silencing of CCT4 in human cells leads to defective endosomal trafficking, and this defect can be rescued by the dynamin activator Ryngo 1-23. These results suggest that the cytosolic chaperonin CCT may regulate vesicle trafficking by promoting the folding of dynamin in addition to its known substrate tubulin. Our findings establish an essential role for the CCT chaperonin in regulating vesicle trafficking, and provide new insights into the regulation of vesicle trafficking and the cellular function of the cytosolic chaperonin.

Cdc37 as a Co-chaperone to Hsp90.

The co-chaperone p50/Cdc37 is an important partner for Hsp90, assisting in molecular chaperone activities, particularly with regard to the regulation of protein kinases. Analysis of the structure of Hsp90-Cdc37-kinase complexes demonstrates the way in which Cdc37 interacts with and controls the folding of a large proportion of intracellular protein kinases. This co-chaperone thus stands at the hub of a multitude of intracellular signaling networks. Indeed, the influence of Cdc37 reaches beyond the housekeeping pathways of protein folding into the regulation of a wide range of cellular processes. This co-chaperone has attracted attention as a potential intermediate in carcinogenesis. Cdc37 is an attractive potential target in cancer due to (1) high expression in a number of tumor types and (2) control of multiple signaling pathways. These properties indicate (3) a potential for selectivity due to its elevated expression in malignant cells and (4) robustness, as the co-chaperone may control multiple growth signaling pathways and thus be less prone to evolution of resistance than less versatile oncoproteins. Cdc37 may also be involved in other aspects of pathophysiology and has been shown to be secreted in exosomes. Protein aggregation disorders have been linked to age-related declines in molecular chaperones and co-chaperones. Cdc37 also appears to be a potential agent in longevity due to its links to protein folding and autophagy, and it will be informative to study the role of Cdc37 maintenance/decline in aging organisms.

HSP90-CDC37-PP5 forms a structural platform for kinase dephosphorylation.

Activation of client protein kinases by the HSP90 molecular chaperone system is affected by phosphorylation at multiple sites on HSP90, the kinase-specific co-chaperone CDC37, and the kinase client itself. Removal of regulatory phosphorylation from client kinases and their release from the HSP90-CDC37 system depends on the Ser/Thr phosphatase PP5, which associates with HSP90 via its N-terminal TPR domain. Here, we present the cryoEM structure of the oncogenic protein kinase client BRAFV600E bound to HSP90-CDC37, showing how the V600E mutation favours BRAF association with HSP90-CDC37. Structures of HSP90-CDC37-BRAFV600E complexes with PP5 in autoinhibited and activated conformations, together with proteomic analysis of its phosphatase activity on BRAFV600E and CRAF, reveal how PP5 is activated by recruitment to HSP90 complexes. PP5 comprehensively dephosphorylates client proteins, removing interaction sites for regulatory partners such as 14-3-3 proteins and thus performing a 'factory reset' of the kinase prior to release.

HSP90-CDC37 functions as a chaperone for the oncogenic FGFR3-TACC3 fusion.

The FGFR3-TACC3 (F3-T3) fusion gene was discovered as an oncogenic molecule in glioblastoma and bladder cancers, and has subsequently been found in many cancer types. Notably, F3-T3 was found to be highly expressed in both untreated and matched recurrence glioblastoma under the concurrent radiotherapy and temozolomide (TMZ) treatment, suggesting that targeting F3-T3 is a valid strategy for treatment. Here, we show that the F3-T3 protein is a client of heat shock protein 90 (HSP90), forming a ternary complex with the cell division cycle 37 (CDC37). Deprivation of HSP90 or CDC37 disrupts the formation of the ternary complex, which destabilizes glycosylated F3-T3, and thereby suppresses F3-T3 oncogenic activity. Gliomas harboring F3-T3 are resistant to TMZ chemotherapy. HSP90 inhibitors sensitized F3-T3 glioma cells to TMZ via the inhibition of F3-T3 activation and potentiated TMZ-induced DNA damage. These results demonstrate that F3-T3 oncogenic function is dependent on the HSP90 chaperone system and suggests a new clinical option for targeting this genetic aberration in cancer.

Overexpression of chaperonin containing TCP1 subunit 7 has diagnostic and prognostic value for hepatocellular carcinoma.

Chaperonin containing TCP1 subunit 7 (CCT7) regulates the expression of many tumor-related proteins. We investigated the diagnostic and prognostic value of CCT7 expression for hepatocellular carcinoma (HCC). In datasets from The Cancer Genome Atlas and the Gene Expression Omnibus, CCT7 mRNA levels were greater in HCC tissues than adjacent normal tissues, and these results were validated using immunohistochemistry. In patients with early-stage disease and low alpha-fetoprotein expression, CCT7 expression was still higher in HCC tissues than normal tissues. Receiver operating characteristic curve analyses indicated that CCT7 expression had better diagnostic value than alpha-fetoprotein for HCC patients with early-stage disease and low alpha-fetoprotein expression. The positive predictive value of CCT7 expression was higher than that of alpha-fetoprotein expression. Higher CCT7 mRNA and protein levels were independent risk factors for poorer overall and recurrence-free survival in HCC patients. Greater methylation of the CpG site cg19515186 was associated with better overall survival in HCC patients. Genes co-expressed with CCT7 were upregulated in HCC and associated with poorer overall survival. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analyses demonstrated that CCT7 expression correlated with spliceosome signaling. These findings demonstrate that CCT7 has diagnostic and prognostic value for HCC.

Okicamelliaside targets the N-terminal chaperone pocket of HSP90 disrupts the chaperone protein interaction of HSP90-CDC37 and exerts antitumor activity.

Heat shock protein 90 (HSP90) has been recognized as a crucial target in cancer cells. However, various toxic reactions targeting the ATP binding site of HSP90 may not be the best choice for HSP90 inhibitors. In this paper, an ellagic acid derivative, namely, okicamelliaside (OCS), with antitumor effects was found. To identify potential anti-cancer mechanisms, an OCS photosensitive probe was applied to target fishing and tracing. Chemical proteomics and protein-drug interaction experiments have shown that HSP90 is a key target for OCS, with a strong binding affinity (KD = 6.45 µM). Mutation analysis of the target protein and molecular dynamics simulation revealed that OCS could competitively act on the key Glu-47 site at the N-terminal chaperone pocket of HSP90, where the co-chaperone CDC37 binds to HSP90, affect its stability and reduce the ∆Gbind of HSP90-CDC37. It was demonstrated that OCS destroys the protein-protein interactions of HSP90-CDC37; selectively affects downstream kinase client proteins of HSP90, including CDK4, P-AKT473, and P-ERK1/2; and exerts antitumor effects on A549 cells. Furthermore, tumor xenograft experiments demonstrated high antitumor activity and low toxicity of OCS in the same way. Our findings identified a novel N-terminal chaperone pocket natural inhibitor of HSP90, that is, OCS, which selectively inhibits the formation of the HSP90-CDC37 protein complex, and provided further insight into HSP90 inhibitors for anti-cancer candidate drugs.

(20S) Ginsenoside Rh2 Exerts Its Anti-Tumor Effect by Disrupting the HSP90A-Cdc37 System in Human Liver Cancer Cells.

(20S) ginsenoside Rh2 (G-Rh2), a major bioactive metabolite of ginseng, effectively inhibits the survival and proliferation of human liver cancer cells. However, its molecular targets and working mechanism remain largely unknown. Excitingly, we screened out heat shock protein 90 alpha (HSP90A), a key regulatory protein associated with liver cancer, as a potential target of (20S) G-Rh2 by phage display analysis and mass spectrometry. The molecular docking and thermal shift analyses demonstrated that (20S) G-Rh2 directly bound to HSP90A, and this binding was confirmed to inhibit the interaction between HSP90A and its co-chaperone, cell division cycle control protein 37 (Cdc37). It is well-known that the HSP90A-Cdc37 system aids in the folding and maturation of cyclin-dependent kinases (CDKs). As expected, CDK4 and CDK6, the two G0-G1 phase promoting kinases as well as CDK2, a key G1-S phase transition promoting kinase, were significantly downregulated with (20S) G-Rh2 treatment, and these downregulations were mediated by the proteasome pathway. In the same condition, the cell cycle was arrested at the G0-G1 phase and cell growth was inhibited significantly by (20S) G-Rh2 treatment. Taken together, this study for the first time reveals that (20S) G-Rh2 exerts its anti-tumor effect by targeting HSP90A and consequently disturbing the HSP90A-Cdc37 chaperone system. HSP90A is frequently overexpressed in human hepatoma cells and the higher expression is closely correlated to the poor prognosis of liver cancer patients. Thus, (20S) G-Rh2 might become a promising alternative drug for liver cancer therapy.

Functional assessment of the V390F mutation in the CCTδ subunit of chaperonin containing tailless complex polypeptide 1.

The chaperonin containing tailless complex polypeptide 1 (CCT) is a multi-subunit molecular chaperone. It is found in the cytoplasm of all eukaryotic cells, where the oligomeric form plays an essential role in the folding of predominantly the cytoskeletal proteins actin and tubulin. Both the CCT oligomer and monomeric subunits also display functions that extend beyond folding, which are often associated with microtubules and actin filaments. Here, we assess the functional significance of the CCTδ V390F mutation, reported in several cancer cell lines. Upon transfection into B16F1 mouse melanoma cells, GFP-CCTδV390F incorporates into the CCT oligomer more readily than GFP-CCTδ. Furthermore, unlike GFP-CCTδ, GFP-CCTδV390F does not interact with the dynactin complex component, p150Glued. As CCTδ has previously been implicated in altered migration in wound healing assays, we assessed the behaviour of GFP-CCTδV390F and other mutants of CCTδ, previously used to assess functional interactions with p150Glued, in chemotaxis assays. We developed the assay system to incorporate a layer of the inert hydrogel GrowDex® to provide a 3D matrix for chemotaxis assessment and found subtle differences in the migration of B16F1 cells, depending on the presence of the hydrogel.

Hsp90 chaperone code and the tumor suppressor VHL cooperatively regulate the mitotic checkpoint.

Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes that plays a vital role in protecting and maintaining the functional integrity of deregulated signaling proteins in tumors. We have previously reported that the stability and activity of the mitotic checkpoint kinase Mps1 depend on Hsp90. In turn, Mps1-mediated phosphorylation Hsp90 regulates its chaperone function and is essential for the mitotic arrest. Cdc14-assisted dephosphorylation of Hsp90 is vital for the mitotic exit. Post-translational regulation of Hsp90 function is also known as the Hsp90 "Chaperone Code." Here, we demonstrate that only the active Mps1 is ubiquitinated on K86, K827, and K848 by the tumor suppressor von Hippel-Lindau (VHL) containing E3 enzyme, in a prolyl hydroxylation-independent manner and degraded in the proteasome. Furthermore, we show that this process regulates cell exit from the mitotic checkpoint. Collectively, our data demonstrates an interplay between the Hsp90 chaperone and VHL degradation machinery in regulating mitosis.

Chaperonin point mutation enhances cadmium endurance in Saccharomyces cerevisiae.

OBJECTIVE: To study the effect of the mutation in conserved G412E in Cct7p subunit of CCT complex on its cellular fate. RESULTS: TriC/CCT is a dynamic multimeric protein that assists in protein folding in an energy-dependent manner. A point mutation in the ATP binding pocket in the equatorial domain of the Cct7p subunit delays the doubling time. The cell size was twice the wild type, and the formation of protein aggregates suggests disturbed folding of the proteins. Upon growing in stressful conditions of arsenous acid and cadmium chloride, the mutant was lethal in As3+ but grew well in Cd2+ with 10.5 µg cadmium uptake mg-1 compared to the wild type. The increased expression of vacuole transporters YCF1 and BPT1 by ten-fold and two-fold in mutant indicates the metal transportation to the vacuole. CONCLUSION: CCT complex was vulnerable to the mutation in G412E in the Cct7p subunit of protein folding molecular machinery. Interestingly, already stressed cells provided robustness against oxidative stress and cadmium sequestration in the vacuole.

A phosphorylation of RIPK3 kinase initiates an intracellular apoptotic pathway that promotes prostaglandin2α-induced corpus luteum regression.

Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) normally signals to necroptosis by phosphorylating MLKL. We report here that when the cellular RIPK3 chaperone Hsp90/CDC37 level is low, RIPK3 also signals to apoptosis. The apoptotic function of RIPK3 requires phosphorylation of the serine 165/threonine 166 sites on its kinase activation loop, resulting in inactivation of RIPK3 kinase activity while gaining the ability to recruit RIPK1, FADD, and caspase-8 to form a cytosolic caspase-activating complex, thereby triggering apoptosis. We found that PGF2α induces RIPK3 expression in luteal granulosa cells in the ovary to cause luteal regression through this RIPK3-mediated apoptosis pathway. Mice carrying homozygous phosphorylation-resistant RIPK3 S165A/T166A knockin mutations failed to respond to PGF2α but retained pro-necroptotic function, whereas mice with phospho-mimicking S165D/T166E homozygous knock-in mutation underwent spontaneous apoptosis in multiple RIPK3-expressing tissues and died shortly after birth. Thus, RIPK3 signals to either necroptosis or apoptosis depending on its serine 165/threonine 166 phosphorylation status.

Bardet-Biedl syndrome proteins regulate intracellular signaling and neuronal function in patient-specific iPSC-derived neurons.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and is characterized by hyperphagic obesity. To investigate the molecular basis of obesity in human BBS, we developed a cellular model of BBS using induced pluripotent stem cell-derived (iPSC-derived) hypothalamic arcuate-like neurons. BBS mutations BBS1M390R and BBS10C91fsX95 did not affect neuronal differentiation efficiency but caused morphological defects, including impaired neurite outgrowth and longer primary cilia. Single-cell RNA sequencing of BBS1M390R hypothalamic neurons identified several downregulated pathways, including insulin and cAMP signaling and axon guidance. Additional studies demonstrated that BBS1M390R and BBS10C91fsX95 mutations impaired insulin signaling in both human fibroblasts and iPSC-derived neurons. Overexpression of intact BBS10 fully restored insulin signaling by restoring insulin receptor tyrosine phosphorylation in BBS10C91fsX95 neurons. Moreover, mutations in BBS1 and BBS10 impaired leptin-mediated p-STAT3 activation in iPSC-derived hypothalamic neurons. Correction of the BBS mutation by CRISPR rescued leptin signaling. POMC expression and neuropeptide production were decreased in BBS1M390R and BBS10C91fsX95 iPSC-derived hypothalamic neurons. In the aggregate, these data provide insights into the anatomic and functional mechanisms by which components of the BBSome in CNS primary cilia mediate effects on energy homeostasis.

Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway.

HER2 breast cancer (BC) remains a significant problem in patients with locally advanced or metastatic BC. We investigated the relationship between T helper 1 (Th1) immune response and the proteasomal degradation pathway (PDP), in HER2-sensitive and -resistant cells. HER2 overexpression is partially maintained because E3 ubiquitin ligase Cullin5 (CUL5), which degrades HER2, is frequently mutated or underexpressed, while the client-protective co-chaperones cell division cycle 37 (Cdc37) and heat shock protein 90 (Hsp90) are increased translating to diminished survival. The Th1 cytokine interferon (IFN)-γ caused increased CUL5 expression and marked dissociation of both Cdc37 and Hsp90 from HER2, causing significant surface loss of HER2, diminished growth, and induction of tumor senescence. In HER2-resistant mammary carcinoma, either IFN-γ or Th1-polarizing anti-HER2 vaccination, when administered with anti-HER2 antibodies, demonstrated increased intratumor CUL5 expression, decreased surface HER2, and tumor senescence with significant therapeutic activity. IFN-γ synergized with multiple HER2-targeted agents to decrease surface HER2 expression, resulting in decreased tumor growth. These data suggest a novel function of IFN-γ that regulates HER2 through the PDP pathway and provides an opportunity to impact HER2 responses through anti-tumor immunity.

Bardet-Biedl syndrome presenting with laryngeal web and bifid epiglottis.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterised by rod-cone dystrophy, obesity, postaxial polydactyly, cognitive impairment, hypogonadism, renal abnormalities, and rarely, laryngeal webs or bifid epiglottis. Most patients present with obesity. Multiple genes are involved in causation of BBS and there is also evidence of triallelic inheritance. We herein report an Asian boy who had weak cry and stridor since birth, and on evaluation was found to have both laryngeal web and bifid epiglottis. Mutation analysis revealed a homozygous variant in BBS10 gene.

Ciliopathies: Coloring outside of the lines.

Ciliopathy syndromes are a diverse spectrum of disease characterized by a combination of cystic kidney disease, hepatobiliary disease, retinopathy, skeletal dysplasia, developmental delay, and brain malformations. Though generally divided into distinct disease categories based on the pattern of system involvement, ciliopathy syndromes are known to display certain phenotypic overlap. We performed next-generation sequencing panel testing, clinical exome sequencing, and research-based exome sequencing reanalysis on patients with suspected ciliopathy syndromes with additional features. We identified biallelic pathogenic variants in BBS1 in a child with features of cranioectodermal dysplasia, and biallelic variants in BBS12 in a child with the clinical stigmata of Bardet-Biedl syndrome, but also with anal atresia. We additionally identified biallelic pathogenic variants in WDR35 and DYNC2H1 in children with predominant liver disease and ductal plate malformation without skeletal dysplasia. Our study highlights the phenotypic and genetic diversity of ciliopathy syndromes, the importance of considering ciliopathy syndromes as a disease-spectrum and screening for all associated complications in all patients, and describes exclusive extra-skeletal manifestations in two classical skeletal dysplasia syndromes.

TEM and STEM-EDS evaluation of metal nanoparticle encapsulation in GroEL/GroES complexes according to the reaction mechanism of chaperonin.

Escherichia coli chaperonin GroEL, which is a large cylindrical protein complex comprising two heptameric rings with cavities of 4.5 nm each in the center, assists in intracellular protein folding with the aid of GroES and adenosine triphosphate (ATP). Here, we investigated the possibility that GroEL can also encapsulate metal nanoparticles (NPs) up to ∼5 nm in diameter into the cavities with the aid of GroES and ATP. The slow ATP-hydrolyzing GroELD52A/D398A mutant, which forms extremely stable complexes with GroES (half-time of ∼6 days), made it possible to analyze GroEL/GroES complexes containing metal NPs. Scanning transmission electron microscopy-energy-dispersive X-ray spectroscopy analysis proved distinctly that FePt NPs and Au NPs were encapsulated in the GroEL/GroES complexes. Dynamic light scattering measurements showed that the NPs in the GroEL/GroES complex were able to maintain their dispersibility in solution. We previously described that the incubation of GroEL and GroES in the presence of ATP·BeFx and adenosine diphosphate·BeFx resulted in the formation of symmetric football-shaped and asymmetric bullet-shaped complexes, respectively. Based on this knowledge, we successfully constructed the football-shaped complex in which two compartments were occupied by Pt or Au NPs (first compartment) and FePt NPs (second compartment). This study showed that metal NPs were sequentially encapsulated according to the GroEL reaction in a step-by-step manner. In light of these results, chaperonin can be used as a tool for handling nanomaterials.

Ciliopathies and the Kidney: A Review.

Primary cilia are specialized sensory organelles that protrude from the apical surface of most cell types. During the past 2 decades, they have been found to play important roles in tissue development and signal transduction, with mutations in ciliary-associated proteins resulting in a group of diseases collectively known as ciliopathies. Many of these mutations manifest as renal ciliopathies, characterized by kidney dysfunction resulting from aberrant cilia or ciliary functions. This group of overlapping and genetically heterogeneous diseases includes polycystic kidney disease, nephronophthisis, and Bardet-Biedl syndrome as the main focus of this review. Renal ciliopathies are characterized by the presence of kidney cysts that develop due to uncontrolled epithelial cell proliferation, growth, and polarity, downstream of dysregulated ciliary-dependent signaling. Due to cystic-associated kidney injury and systemic inflammation, cases result in kidney failure requiring dialysis and transplantation. Of the handful of pharmacologic treatments available, none are curative. It is important to determine the molecular mechanisms that underlie the involvement of the primary cilium in cyst initiation, expansion, and progression for the development of novel and efficacious treatments. This review updates research progress in defining key genes and molecules central to ciliogenesis and renal ciliopathies.