Dataset Information

Avian Chaperonin Containing TCP1 Subunit 5 Supports Influenza A Virus Replication by Interacting With Viral Nucleoprotein, PB1, and PB2 Proteins.

ABSTRACT: Humans and avian species are prone to influenza viral infection, which may cause serious clinical consequences. Many studies have documented the critical role of host factors in the influenza virus life cycle based on human models, but knowledge about their roles in birds is very limited. In this study, using immunoprecipitation coupled with mass spectrometry, a total of 72 potential interacting proteins of influenza nucleoprotein (NP) were identified in DF-1 cells. Among these proteins, avian chaperonin containing TCP1 subunit 5 (CCT5) was demonstrated to interact with influenza A virus (IAV) NP directly, as well as polymerase basic protein 1 (PB1) and polymerase basic protein 2 (PB2) but not with polymerase acidic protein (PA). Further investigation showed that viral infection profoundly elevated the expression level of cellular CCT5, whose expression, in turn, promoted the nuclear export of NP, as well as viral polymerase activity, thereby facilitating the replication of IAV. The obtained results suggested an important role of avian CCT5 in supporting influenza virus replication, which may serve as an anti-influenza target.

SUBMITTER: Zhang X

PROVIDER: S-EPMC7593399 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Avian Chaperonin Containing TCP1 Subunit 5 Supports Influenza A Virus Replication by Interacting With Viral Nucleoprotein, PB1, and PB2 Proteins.

Zhang Xiaohan X Lin Xian X Qin Chenghuang C Huang Kun K Sun Xiaomei X Zhao Lianzhong L Jin Meilin M

Frontiers in microbiology 20201015

Humans and avian species are prone to influenza viral infection, which may cause serious clinical consequences. Many studies have documented the critical role of host factors in the influenza virus life cycle based on human models, but knowledge about their roles in birds is very limited. In this study, using immunoprecipitation coupled with mass spectrometry, a total of 72 potential interacting proteins of influenza nucleoprotein (NP) were identified in DF-1 cells. Among these proteins, avian c ...[more]

PMID: 33178142

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Project description:Herein we report the use of Chaperonin-Containing TCP-1 (CCT or TRiC) as a marker to detect circulating tumor cells (CTCs) that are shed from tumors during oncogenesis. Most detection methods used in liquid biopsy approaches for enumeration of CTCs from blood, employ epithelial markers like cytokeratin (CK). However, such markers provide little information on the potential of these shed tumor cells, which are normally short-lived, to seed metastatic sites. To identify a marker that could go beyond enumeration and provide actionable data on CTCs, we evaluated CCT. CCT is a protein-folding complex composed of eight subunits. Previously, we found that expression of the second subunit (CCT2 or CCTβ) inversely correlated with cancer patient survival and was essential for tumorigenesis in mice, driving tumor-promoting processes like proliferation and anchorage-independent growth. In this study, we examined CCT2 expression in cancer compared to normal tissues and found statistically significant increases in tumors. Because not all blood samples from cancer patients contain detectable CTCs, we used the approach of spiking a known number of cancer cells into blood from healthy donors to test a liquid biopsy approach using CCT2 to distinguish rare cancer cells from the large number of non-cancer cells in blood. Using a clinically validated method for capturing CTCs, we evaluated detection of intracellular CCT2 staining for visualization of breast cancer and small cell lung (SCLC) cancer cells. We demonstrated that CCT2 staining could be incorporated into a CTC capture and staining protocol, providing biologically relevant information to improve detection of cancer cells shed in blood. These results were confirmed with a pilot study of blood from SCLC patients. Our studies demonstrate that detection of CCT2 could identify rare cancer cells in blood and has application in liquid biopsy approaches to enhance the use of minimally invasive methods for cancer diagnosis.

Project description:Uncontrolled proliferation as a result of dysregulated cell cycling is one of the hallmarks of cancer. Therapeutically targeting pathways that control the cell cycle would improve patient outcomes. However, the development of drug resistance and a limited number of inhibitors that target multiple cell cycle modulators are challenges that impede stopping the deregulated growth that leads to malignancy. To advance the discovery of new druggable targets for cell cycle inhibition, we investigated the role of Chaperonin-Containing TCP1 (CCT or TRiC) in breast cancer cells. CCT, a type II chaperonin, is a multi-subunit protein-folding complex that interacts with many oncoproteins and mutant tumor suppressors. CCT subunits are highly expressed in a number of cancers, including breast cancer. We found that expression of one of the CCT subunits, CCT2, inversely correlates with breast cancer patient survival and is subject to copy number alterations through genomic amplification. To investigate a role for CCT2 in the regulation of the cell cycle, we expressed an exogenous CCT2-FLAG construct in T47D and MCF7 luminal A breast cancer cells and examined cell proliferation under conditions of two-dimensional (2D) monolayer and three-dimensional (3D) spheroid cultures. Exogenous CCT2 increased the proliferation of cancer cells, resulting in larger and multiple spheroids as compared to control cells. CCT2-expressing cells were also able to undergo spheroid growth reversal, re-attaching, and resuming growth in 2D cultures. Such cells gained anchorage-independent growth. CCT2 expression in cells correlated with increased expression of MYC, especially in spheroid cultures, and other cell cycle regulators like CCND1 and CDK2, indicative of a novel activity that could contribute to the increase in cell growth. Statistically significant correlations between CCT2, MYC, and CCND1 were shown. Since CCT2 is located on chromosome 12q15, an amplicon frequently found in soft tissue cancers as well as breast cancer, CCT2 may have the basic characteristics of an oncogene. Our findings suggest that CCT2 could be an essential driver of cell division that may be a node through which pathways involving MYC, cyclin D1 and other proliferative factors could converge. Hence the therapeutic inhibition of CCT2 may have the potential to achieve multi-target inhibition, overcoming the limitations associated with single agent inhibitors.

Dataset Information

Avian Chaperonin Containing TCP1 Subunit 5 Supports Influenza A Virus Replication by Interacting With Viral Nucleoprotein, PB1, and PB2 Proteins.

Publications

Avian Chaperonin Containing TCP1 Subunit 5 Supports Influenza A Virus Replication by Interacting With Viral Nucleoprotein, PB1, and PB2 Proteins.

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