A Role for CD81 and Hepatitis C Virus in Hepatoma Mobility

Brimacombe, Claire L.; Wilson, Garrick K.; Hübscher, Stefan G.; McKeating, Jane A.; Farquhar, Michelle J.

doi:10.3390/v6031454

Cited by 10 publications

(12 citation statements)

References 59 publications

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“…In the current study, we describe the isolated network of the plasma membrane protein CD81. This tetraspanin functions in cell motility and in confirmation we found integrins, small G proteins, GTPases and growth factor receptors involved in cell migration as CD81 network molecules [39]. To our current knowledge, HCV uses only two of these molecules (EGFR, ITGB1) for cell entry and Plasmodium presumably none of the molecules involved in cell migration.…”

Section: Implications For the Understanding Of Liver Pathogenesis Andsupporting

confidence: 78%

“…In the absence of infection CD81 is thought to regulate migration of liver cells [39]. In confirmation of this notion, in silico analysis maps here identified CD81 network proteins to cellular movement pathways.…”

Section: The Cd81 Network Protein Cblb As Virus Entry Facilitatorsupporting

confidence: 74%

“…In B lymphocytes CD81 serves as a clamp for the B cell receptor complex [37,38]. In liver cells only little information on the CD81 guided membrane protein complexes is available and this is reflected by a limited knowledge on endogenous CD81 functions in the liver [15,39]. Here, we identified 33 CD81 associated proteins and their relative strength of interaction with CD81 as determined by abundance in CD81 co-IPs (depicted in a centered network in S3A Fig) plus nine closest neighbor network proteins.…”

Section: Cd81 Organizes Tyrosine Kinase and Small G Protein Signalingmentioning

confidence: 99%

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Hepatitis C virus enters liver cells using the CD81 receptor complex proteins calpain-5 and CBLB

et al. 2018

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Hepatitis C virus (HCV) and the malaria parasite Plasmodium use the membrane protein CD81 to invade human liver cells. Here we mapped 33 host protein interactions of CD81 in primary human liver and hepatoma cells using high-resolution quantitative proteomics. In the CD81 protein network, we identified five proteins which are HCV entry factors or facilitators including epidermal growth factor receptor (EGFR). Notably, we discovered calpain-5 (CAPN5) and the ubiquitin ligase Casitas B-lineage lymphoma proto-oncogene B (CBLB) to form a complex with CD81 and support HCV entry. CAPN5 and CBLB were required for a post-binding and pre-replication step in the HCV life cycle. Knockout of CAPN5 and CBLB reduced susceptibility to all tested HCV genotypes, but not to other enveloped viruses such as vesicular stomatitis virus and human coronavirus. Furthermore, Plasmodium sporozoites relied on a distinct set of CD81 interaction partners for liver cell entry. Our findings reveal a comprehensive CD81 network in human liver cells and show that HCV and Plasmodium highjack selective CD81 interactions, including CAPN5 and CBLB for HCV, to invade cells.

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Section: Implications For the Understanding Of Liver Pathogenesis Andsupporting

confidence: 78%

Section: The Cd81 Network Protein Cblb As Virus Entry Facilitatorsupporting

confidence: 74%

Section: Cd81 Organizes Tyrosine Kinase and Small G Protein Signalingmentioning

confidence: 99%

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Hepatitis C virus enters liver cells using the CD81 receptor complex proteins calpain-5 and CBLB

et al. 2018

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“…Experiments using CD81knockout mice have shown that CD81 is not essential for the development of T and B lymphocytes, but may play an important role in the proliferation and proper immune response of B cells [7,8]. In addition, it has been suggested that CD81 may regulate mitosis [9] and enhance the motility and metastatic potential of hepatocarcinoma and malignant melanoma cells [10,11]. CD81 has also attracted attention as an exosome biomarker [12] and, as such, novel anticancer drugs that can inhibit CD81 may offer therapeutic potential.…”

Section: Introductionmentioning

confidence: 99%

The tetraspanin CD81 mediates the growth and metastases of human osteosarcoma

et al. 2019

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Purpose CD81 is a member of the tetraspanin family of membrane proteins. Recently, it has been shown that CD81 may be involved in cancer cell proliferation and metastasis. As yet, however, there have been few reports on the expression and role of CD81 in osteosarcoma. Methods The expression of CD81 was investigated in human osteoblast cell line hFOB1.19 and in human osteosarcoma cell lines Saos2, MG63 and 143B. The expression of CD81 was inhibited in osteosarcoma cells using siRNA after which cell proliferation, migration and invasion were assessed. We also used Western blotting to investigate the phosphorylation status of Akt, Erk, JNK and p38, and measured the expression of MMP-2, MMP-9 and MT1-MMP. In addition, we used a CRISPR/Cas9 system to stably knock out CD81 expression in 143B cells, transplanted the cells into mice, and assessed tumor formation and lung metastasis in these mice compared to those in the control group. Results We found that CD81 was expressed in the human osteoblast cell line and in all osteosarcoma cell lines tested. The osteosarcoma cell line 143B exhibited a particularly high level of expression. In addition, we found that osteosarcoma cell proliferation, migration and invasion were decreased after CD81 inhibition, and that the phosphorylation of Akt and Erk was suppressed. Also, the expression levels of MMP-2, MMP-9 and MT1-MMP were found to be suppressed, with MMP-9 showing the greatest suppression. In vivo, we found that mice transplanted with CD81 knockout 143B cells exhibited significantly less tumor formation and lung metastasis than mice in the control group. Conclusion Based on our findings we conclude that inhibition of CD81 suppresses intracellular signaling and reduces tumorigenesis and lung metastasis in osteosarcoma cells.

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“…CD81 performs this role via partnership with CD19; first by chaperoning CD19 through the secretory pathway and then by dictating its cell surface distribution, which permits proper assembly of the B-cell receptor complex upon activation [9][10][11][12]. Through other molecular partnerships CD81 has been implicated in additional physiological processes such as T-cell receptor signalling, cell migration, growth factor signalling, sperm-egg fusion and most recently, biological ageing [13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Cholesterol sensing by CD81 is important for hepatitis C virus entry

Palor

Stejskal

Mandal

et al. 2019

Preprint

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a These authors contributed equally to this work CD81 is a multifunctional protein that plays a central role in both physiological and pathological processes. Recent structural analysis of CD81 indicates that it adopts a compact fold with its large extracellular loop sitting close to the plasma membrane; however, there is evidence that CD81 can undergo a conformational switch where the extracellular loop flips into an extended open conformation. We investigated the relevance of CD81 conformational switching to its function as a receptor for hepatitis C virus (HCV). Structure-led mutagenesis was used to generate CD81 variants with altered conformational switching. Each variant maintained proper protein folding and expression, and retained a basic function: the ability to chaperone CD19 to the cell surface. We then used multiple systems to evaluate HCV receptor activity; in these experiments 'open' CD81 variants exhibited consistently poor receptor function, whereas a 'closed' CD81 displayed enhanced ability to support HCV entry. We sought to corroborate these findings by exploring CD81 structural flexibility using molecular dynamics simulations. These experiments were in excellent agreement with our in vitro work, with 'open' CD81 variants having a propensity to undergo conformational switching. Taken together, we provide evidence for a conformational switch in CD81 that regulates its HCV receptor activity. This work furthers our understanding of the molecular mechanism of HCV entry and is relevant to CD81's other functions in health and disease.

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A Role for CD81 and Hepatitis C Virus in Hepatoma Mobility

Cited by 10 publications

References 59 publications

Hepatitis C virus enters liver cells using the CD81 receptor complex proteins calpain-5 and CBLB

Hepatitis C virus enters liver cells using the CD81 receptor complex proteins calpain-5 and CBLB

The tetraspanin CD81 mediates the growth and metastases of human osteosarcoma

Cholesterol sensing by CD81 is important for hepatitis C virus entry

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