Tectonic Proteins Are Important Players in Non-Motile Ciliopathies

Gong, Siyi; Ji, Feng; Wang, Bin; Zhang, Yingying; Xu, Xingshun; Sun, Miao

doi:10.1159/000494017

Cited by 9 publications

(10 citation statements)

References 65 publications

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“…In Figure 2A, heat maps and hierarchical cluster analysis demonstrated a correlation between C militaris –induced apoptosis, and TCTN3 protein expression in C militaris –treated NSCLC cells. Tectonic proteins including TCTN1, TCTN2, and TCTN3 are important component proteins residing at the transition zone (TZ) of cilia, 45 and these are necessary for transduction of the SHH signaling pathway, as revealed by abnormal processing of GLI3 in patient cells. 46 Therefore, we confirmed whether tectonic and HH signaling pathway–related, including TCTN3, were reduced by C militaris .…”

Section: Resultsmentioning

confidence: 99%

“…More important, tectonic proteins play a vital role in the regulation of the SHH pathway. 45 Also, tectonic proteins are an upstream gene involved in embryonic development. The aim of the further study is to investigate the effect of the tectonic proteins gene on the viability and Cordyceps militaris suppresses GLI1 transcriptional activity via suppression of SMO/ PTCH1 signaling (A) Effect of SMO/PTCH1 signaling on nuclear translocation of GLI1 in C militaris A549 cells.…”

Section: Discussionmentioning

confidence: 99%

“…In Figure 2A, heat maps and hierarchical cluster analysis demonstrated a correlation between C militaris-induced apoptosis, and TCTN3 protein expression in C militaristreated NSCLC cells. Tectonic proteins including TCTN1, TCTN2, and TCTN3 are important component proteins residing at the transition zone (TZ) of cilia, 45 and these Protein-protein interaction network analysis of gene expression in C militaris-treated A549 via STRING v11 (Input genes: Smoothened signaling related genes including PTCH2, GLI2, TGFBR2, TMEM231, TMEM17, DZIP1, TCTN2, DISP2, GLI3, CENPJ, CC2D2A, TCTN3, EVC2, BMP4, PTCH1, STIL, HSPB11, TCTN3). (C) Biological processes, cellular component, and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis about protein-protein interaction network analysis.…”

Section: Protein-protein Interaction and Gene Ontology Analysis In Cordyceps Militaris-treated Nsclc Cellsmentioning

confidence: 99%

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Cordyceps militaris Exerts Anticancer Effect on Non–Small Cell Lung Cancer by Inhibiting Hedgehog Signaling via Suppression of TCTN3

Jang

Shen

et al. 2020

Integr Cancer Ther

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This study aimed to investigate the effect of Cordyceps militaris extract on the proliferation and apoptosis of non–small cell lung cancer (NSCLC) cells and determine the underlying mechanisms. We performed a CCK-8 assay to detect cell proliferation, detection of morphological changes through transmission electron microscopy (TEM), annexin V–FITC/PI double staining to analyze apoptosis, and immunoblotting to measure the protein expression of apoptosis and hedgehog signaling–related proteins, with C militaris treated NSCLC cells. In this study, we first found that C militaris reduced the viability and induced morphological disruption in NSCLC cells. The gene expression profiles indicated a reprogramming pattern of genes and transcription factors associated with the action of TCTN3 on NSCLC cells. We also confirmed that the C militaris–induced inhibition of TCTN3 expression affected the hedgehog signaling pathway. Immunoblotting indicated that C militaris–mediated TCTN3 downregulation induced apoptosis in NSCLC cells, involved in the serial activation of caspases. Moreover, we demonstrated that the C militaris negatively modulated GLI1 transcriptional activity by suppressing SMO/PTCH1 signaling, which affects the intrinsic apoptotic pathway. When hedgehog binds to the PTCH1, SMO dissociates from PTCH1 inhibition at cilia. As a result, the active GLI1 translocates to the nucleus. C militaris clearly suppressed GLI1 nuclear translocation, leading to Bcl-2 and Bcl-xL down-regulation. These results suggested that C militaris induced NSCLC cell apoptosis, possibly through the downregulation of SMO/PTCH1 signaling and GLI1 activation via inhibition of TCTN3. Taken together, our findings provide new insights into the treatment of NSCLC using C militaris.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Protein-protein Interaction and Gene Ontology Analysis In Cordyceps Militaris-treated Nsclc Cellsmentioning

confidence: 99%

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Cordyceps militaris Exerts Anticancer Effect on Non–Small Cell Lung Cancer by Inhibiting Hedgehog Signaling via Suppression of TCTN3

Jang

Shen

et al. 2020

Integr Cancer Ther

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“…In addition to SLC -family genes, the TCTN family shows overlap in selection: TCTN3 is a candidate domestication gene in dog, and TCTN1 is a candidate domestication gene in horse (Theofanopoulou et al, 2017). These genes encode proteins that constitute the tectonic-like complex, which is involved in mediating Hedgehog signal transduction as well as protein trafficking (Reiter and Skarnes, 2006; Gong et al, 2018). Expression of the tectonic-like complex is known to be critically important for neural tube development, and mutations in both TCTN3 and TCTN1 result in Joubert syndrome (Huppke et al, 2015; Wang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

An Integrated Model of Minor Intron Emergence and Conservation

2019

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Minor introns constitute <0.5% of the introns in the human genome and have remained an enigma since their discovery. These introns are removed by a distinct splicing complex, the minor spliceosome. Both are ancient, tracing back to the last eukaryotic common ancestor (LECA), which is reflected by minor intron enrichment in specific gene families, such as the mitogen activated-protein kinase kinases, voltage-gated sodium and calcium ion channels, and E2F transcription factors. Most minor introns occur as single introns in genes with predominantly major introns. Due to this organization, minor intron-containing gene (MIG) expression requires the coordinated action of two spliceosomes, which increases the probability of missplicing. Thus, one would expect loss of minor introns via purifying selection. This has resulted in complete minor intron loss in at least nine eukaryotic lineages. However, minor introns are highly conserved in land plants and metazoans, where their importance is underscored by embryonic lethality when the minor spliceosome is inactivated. Conditional inactivation of the minor spliceosome has shown that rapidly dividing progenitor cells are highly sensitive to minor spliceosome loss. Indeed, we found that MIGs were significantly enriched in a screen for genes essential for survival in 341 cycling cell lines. Here, we propose that minor introns inserted randomly into genes in LECA or earlier and were subsequently conserved in genes crucial for cycling cell survival. We hypothesize that the essentiality of MIGs allowed minor introns to endure through the unicellularity of early eukaryotic evolution. Moreover, we identified 59 MIGs that emerged after LECA, and that many of these are essential for cycling cell survival, reinforcing our essentiality model for MIG conservation. This suggests that minor intron emergence is dynamic across eukaryotic evolution, and that minor introns should not be viewed as molecular fossils. We also posit that minor intron splicing was co-opted in multicellular evolution as a regulatory switch for en masse control of MIG expression and the biological processes they regulate. Specifically, this mode of regulation could control cell proliferation and thus body size, an idea supported by domestication syndrome, wherein MIGs are enriched in common candidate animal domestication genes.

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“…We next mapped the localization of PI(4,5)P 2 at the transition zone in hTERT-RPE1 cells relative to transition zone proteins TCTN1, MKS3, RPGRIP1L and AHI1, components of the MKS and NPHP complexes (Gong et al, 2018), and distal appendage protein CEP164 to mark the proximal boundary of the transition zone (Yang et al, 2015). STED resolution imaging was performed for the PI and transition zone protein components and overlayed on a confocal resolution image of the ARL13B stained axoneme (Figure 2A).…”

Section: )P 3 Localize To Distinct Subdomains Of the Transition Zonementioning

confidence: 99%

Superresolution Microscopy Reveals Distinct Phosphoinositide Subdomains Within the Cilia Transition Zone

Conduit

Davies

Fulcher

et al. 2021

Front. Cell Dev. Biol.

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Primary cilia are evolutionary conserved microtubule-based organelles that protrude from the surface of most mammalian cells. Phosphoinositides (PI) are membrane-associated signaling lipids that regulate numerous cellular events via the recruitment of lipid-binding effectors. The temporal and spatial membrane distribution of phosphoinositides is regulated by phosphoinositide kinases and phosphatases. Recently phosphoinositide signaling and turnover has been observed at primary cilia. However, the precise localization of the phosphoinositides to specific ciliary subdomains remains undefined. Here we use superresolution microscopy (2D stimulated emission depletion microscopy) to map phosphoinositide distribution at the cilia transition zone. PI(3,4,5)P3 and PI(4,5)P2 localized to distinct subregions of the transition zone in a ring-shape at the inner transition zone membrane. Interestingly, the PI(3,4,5)P3 subdomain was more distal within the transition zone relative to PtdIns(4,5)P2. The phosphoinositide effector kinase pAKT(S473) localized in close proximity to these phosphoinositides. The inositol polyphosphate 5-phosphatase, INPP5E, degrades transition zone phosphoinositides, however, studies of fixed cells have reported recombinant INPP5E localizes to the ciliary axoneme, distant from its substrates. Notably, here using live cell imaging and optimized fixation/permeabilization protocols INPP5E was found concentrated at the cilia base, in a distribution characteristic of the transition zone in a ring-shaped domain of similar dimensions to the phosphoinositides. Collectively, this superresolution map places the phosphoinositides in situ with the transition zone proteins and reveals that INPP5E also likely localizes to a subdomain of the transition zone membrane, where it is optimally situated to control local phosphoinositide metabolism.

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Tectonic Proteins Are Important Players in Non-Motile Ciliopathies

Cited by 9 publications

References 65 publications

Cordyceps militaris Exerts Anticancer Effect on Non–Small Cell Lung Cancer by Inhibiting Hedgehog Signaling via Suppression of TCTN3

Cordyceps militaris Exerts Anticancer Effect on Non–Small Cell Lung Cancer by Inhibiting Hedgehog Signaling via Suppression of TCTN3

An Integrated Model of Minor Intron Emergence and Conservation

Superresolution Microscopy Reveals Distinct Phosphoinositide Subdomains Within the Cilia Transition Zone

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