The CCT chaperonin is a novel regulator of Ca
            <sup>2+</sup>
            signaling through modulation of Orai1 trafficking

Hodeify, Rawad; Nandakumar, Manjula; Own, Maryam; Courjaret, Raphael Jean; Graumann, Johannes; Hubrack, Satanay; Machaca, Khaled

doi:10.1126/sciadv.aau1935

Cited by 20 publications

(38 citation statements)

References 56 publications

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“…Of all the identified proteins, we were specifically intrigued by the enrichment of CCT2 in UC-MSC-EVs because of its reported modulation of Ca 2+ channels trafficking ( Figure 5B,C). [34,35] Our Western blotting analysis also confirmed that both UC-MSC-EVs and UC-MSCs contained high Figure 2. UC-MSC-EVs improve liver IRI and regulate CD154 expression on CD4+ T cells in vitro and in vivo.…”

Section: Cct2 Derived From Uc-msc-evs Reduces Cd154 Synthesis Of Cd4+supporting

confidence: 67%

Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Protect Liver Ischemia/Reperfusion Injury by Reducing CD154 Expression on CD4+ T Cells via CCT2

Zheng

Zhou

et al. 2020

Advanced Science

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As a cause of postoperative complications and early hepatic failure after liver transplantation, liver ischemia/reperfusion injury (IRI) still has no effective treatment during clinical administration. Although the therapeutic potential of mesenchymal stem cells (MSCs) for liver IRI has been previously shown, the underlying mechanisms are not completely clear. It is accepted that MSC‐derived extracellular vesicles (MSC‐EVs) are newly uncovered messengers for intercellular communication. Herein, it is reported that umbilical cord‐derived MSCs (UC‐MSCs) improve liver IRI in mice through their secreted EVs. It is also visualized that UC‐MSC‐EVs mainly concentrate in liver after 6 h of reperfusion. Furthermore, UC‐MSC‐EVs are found to significantly modulate the membranous expression of CD154 of intrahepatic CD4+ T cells, which is an initiation of inflammatory response in liver and can aggravate liver IRI. Mechanistically, protein mass spectrum analysis is performed and it is revealed that Chaperonin containing TCP1 subunit 2 (CCT2) enriches in UC‐MSC‐EVs, which regulates the calcium channels to affect Ca2+ influx and suppress CD154 synthesis in CD4+ T cells. In conclusion, these results highlight the therapeutic potential of UC‐MSC‐EVs in attenuating liver IRI. This finding suggests that CCT2 from UC‐MSC‐EVs can modulate CD154 expression of intrahepatic CD4+ T cells during liver IRI through the Ca2+‐calcineurin‐NFAT1 signaling pathway.

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Section: Cct2 Derived From Uc-msc-evs Reduces Cd154 Synthesis Of Cd4+supporting

confidence: 67%

Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Protect Liver Ischemia/Reperfusion Injury by Reducing CD154 Expression on CD4+ T Cells via CCT2

Zheng

Zhou

et al. 2020

Advanced Science

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“…Further evidence supporting the important role of CCT in cell cycling come from studies showing that key cell cycle mediators like Cdc20 44 , CDK2/cyclin E 45 , Polo-like kinase 1 (PLK1) 46 and others are folded and assembled by CCT 30,33 , which in part explains why CCT levels increase during S phase 47 . Moreover, the CCT chaperonin was recently found to have role in the disassembly of mitotic checkpoint complexes 48 as well as mediating calcium signaling through Orai1 trafficking 49 . Our finding that overexpressing CCT2 promoted the proliferation of breast cancer and breast epithelial cells is among the first to demonstrate that an increase in cancer cell growth and upregulation of select CDKs as well as other CCT subunits resulted from overexpressing this single CCT subunit.…”

Section: Discussionmentioning

confidence: 99%

Investigating Chaperonin-Containing TCP-1 subunit 2 as an essential component of the chaperonin complex for tumorigenesis

Showalter

Martini

Nierenberg

et al. 2020

Sci Rep

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Chaperonin-containing TCP-1 (CCT or TRiC) is a multi-subunit complex that folds many of the proteins essential for cancer development. CCT is expressed in diverse cancers and could be an ideal therapeutic target if not for the fact that the complex is encoded by eight distinct genes, complicating the development of inhibitors. Few definitive studies addressed the role of specific subunits in promoting the chaperonin's function in cancer. To this end, we investigated the activity of CCT2 (CCTβ) by overexpressing or depleting the subunit in breast epithelial and breast cancer cells. We found that increasing total CCT2 in cells by 1.3-1.8-fold using a lentiviral system, also caused CCT3, CCT4, and CCT5 levels to increase. Likewise, silencing cct2 gene expression by ~50% caused other CCT subunits to decrease. Cells expressing CCT2 were more invasive and had a higher proliferative index. CCT2 depletion in a syngeneic murine model of triple negative breast cancer (TNBC) prevented tumor growth. These results indicate that the CCT2 subunit is integral to the activity of the chaperonin and is needed for tumorigenesis. Hence CCT2 could be a viable target for therapeutic development in breast and other cancers. The hallmarks of cancer (uncontrolled proliferation, genomic instability, metastasis, etc.) reveal the complex nature of this disease and the challenges faced developing effective therapeutics 1,2. Cancer does, however, have an "Achilles heel" and that is its dependency or addiction on major cellular events or processes like transcription, translation, splicing, protein degradation and protein-folding 3. In healthy cells, such conserved and essential processes are rigorously regulated by the proteostasis network (PN) to ensure proteome balance. In order to maintain proteome integrity, the cellular proteome must be synthesized, folded into its native structure, and, when no longer needed, degraded and the amino acids recycled 4,5. Chaperones and chaperonins are key players in the PN 6. Unlike healthy, non-transformed cells, the PN of cancer cells is taxed to produce proteins involved in survival, angiogenesis, migration, proliferation which are essential for tumor formation, progression and metastasis. Cancer cells have a higher dependency on molecular chaperones and are uniquely challenged due to imbalances caused by chromosomal abnormalities and overexpression of oncogenes, ultimately leading to cellular stress 7. As example, inhibitors of Heat Shock Protein 90 (HSP90) showed promising outcomes in the treatment of metastatic breast cancer 8. However, despite being in clinical trials since 1998, the success of HSP90 inhibitors in clinical trials remains mixed 9-11. Reasons such as dose-limiting toxicity, incomplete inhibition of HSP90, and insufficient downregulation of client proteins impeded the clinical use of current HSP90 inhibitors 12,13. In recent years,

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“…A recent study has identified a major role for the intracellular loop in Orai1 involving amino acids 157–167 in regulation of channel trafficking ( 13 ). This region was found to interact with the chaperonin-containing TCP-1 complex (T-complex protein) chaperonin complex to modulate Orai1 endocytosis.…”

Section: Discussionmentioning

confidence: 99%

Single-nucleotide polymorphisms in Orai1 associated with atopic dermatitis inhibit protein turnover, decrease calcium entry and disrupt calcium-dependent gene expression

Yeh¹,

Lin²,

Kramer

et al. 2019

Human Molecular Genetics

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Loss-of function mutations in Orai1 Ca2+ channels lead to a form of severe combined immunodeficiency, auto-immunity, muscle hypotonia and defects in dental enamel production and sweat gland function. Two single-nucleotide polymorphisms (SNPs) in Orai1 have been found and localize to the second extracellular loop. These polymorphisms associate with atopic dermatitis but how they affect Ca2+ signalling and cell function is unknown. Here, we find that Orai1–SNPs turnover considerably more slowly than wild type Orai1 and are more abundantly expressed in the plasma membrane. We show a central role for flotillin in the endocytotic recycling of Orai1 channels and that endocytosed wild type Orai1 is trafficked to Rab 7-positive late endosomes for lysosomal degradation. Orai1–SNPs escape the degradation pathway and instead enter Rab 11-positive recycling endosomes, where they are returned to the surface membrane through Arf6-dependent exocytosis. We find that Orai1–SNPs escape late endosomes through endosomal pH regulation of interaction between the channel and flotillin. We identify a pH-sensitive electrostatic interaction between positively charged arginine in extracellular loop 2 (K210) and a negatively charged aspartate (D112) in extracellular loop 1 that helps determine Orai1 turnover. The increase in membrane Orai1–SNP leads to a mis-match in Orai1–STIM stoichiometry, resulting in inhibition of Ca2+ entry and Ca2+-dependent gene expression. Our results identify new strategies for targeting atopic dermatitis.

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The CCT chaperonin is a novel regulator of Ca ²⁺ signaling through modulation of Orai1 trafficking

Abstract: A chaperone complex (CCT) regulates the trafficking of a calcium channel (Orai1) and, as such, modulates cellular function.

Cited by 20 publications

References 56 publications

Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Protect Liver Ischemia/Reperfusion Injury by Reducing CD154 Expression on CD4+ T Cells via CCT2

Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Protect Liver Ischemia/Reperfusion Injury by Reducing CD154 Expression on CD4+ T Cells via CCT2

Investigating Chaperonin-Containing TCP-1 subunit 2 as an essential component of the chaperonin complex for tumorigenesis

Single-nucleotide polymorphisms in Orai1 associated with atopic dermatitis inhibit protein turnover, decrease calcium entry and disrupt calcium-dependent gene expression

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The CCT chaperonin is a novel regulator of Ca 2+ signaling through modulation of Orai1 trafficking

Abstract: A chaperone complex (CCT) regulates the trafficking of a calcium channel (Orai1) and, as such, modulates cellular function.

Cited by 20 publications

References 56 publications

Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Protect Liver Ischemia/Reperfusion Injury by Reducing CD154 Expression on CD4+ T Cells via CCT2

Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Protect Liver Ischemia/Reperfusion Injury by Reducing CD154 Expression on CD4+ T Cells via CCT2

Investigating Chaperonin-Containing TCP-1 subunit 2 as an essential component of the chaperonin complex for tumorigenesis

Single-nucleotide polymorphisms in Orai1 associated with atopic dermatitis inhibit protein turnover, decrease calcium entry and disrupt calcium-dependent gene expression

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The CCT chaperonin is a novel regulator of Ca ²⁺ signaling through modulation of Orai1 trafficking