Recruitment of Cbl-b to B Cell Antigen Receptor Couples Antigen Recognition to Toll-Like Receptor 9 Activation in Late Endosomes

Veselits, Margaret; Tanaka, Azusa; Lipkowitz, Stanley; O'Neill, Shannon; Sciammas, Roger; Finnegan, Alison; Zhang, Jian; Clark, Marcus R.

doi:10.1371/journal.pone.0089792

Cited by 16 publications

(20 citation statements)

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“…We found that the E3 ligase activity of CBLB is dispensable for promoting HCV uptake. This is in line with an E3 ligase activity independent role of CBLB in B cell receptor internalization [45]. CBLB is known to coordinate EGFR internalization together with CBL, which others and we describe as HCV entry facilitator [29,46].…”

Section: The Cd81 Network Protein Cblb As Virus Entry Facilitatorsupporting

confidence: 88%

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: The Cd81 Network Protein Cblb As Virus Entry Facilitatorsupporting

confidence: 88%

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

et al. 2018

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“…The cDNA encoding human Cbl-b and Cbl-b C373A mutant were subcloned into the plasmid MIGR1 (28). Calcium Phosphate transfection of HEK293T cells with MIGR1 was carried out as previously described (17).…”

Section: Methodsmentioning

confidence: 99%

Protein Tyrosine Phosphatase SHP-1 Modulates T Cell Responses by Controlling Cbl-b Degradation

Xiao

Qiao

Tang

et al. 2015

The Journal of Immunology

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Previously, we demonstrated that CD28 and CTLA-4 signaling controls Cbl-b protein expression, which is critical for T cell activation and tolerance induction. However, the molecular mechanism(s) of this regulation remains to be elucidated. In this study, we found that Cbl-b fails to undergo tyrosine phosphorylation upon CD3 stimulation because SHP-1 is recruited to and dephosphorylates Cbl-b, while CD28 costimulation abrogates this interaction. In support of this finding, T cells lacking SHP-1 display heightened tyrosine phosphorylation and ubiquitination of Cbl-b upon TCR stimulation, which correlates with decreased levels of Cbl-b protein. The aberrant Th2 phenotype observed in T cell-specific Shp1−/− (tShp1−/−) mice is reminiscent of heightened Th2 response in Cblb−/− mice. Indeed, over-expressing Cbl-b in tShp1−/− T cells not only inhibits heightened Th2 differentiation in vitro, but also Th2 responses and allergic airway inflammation in vivo. Therefore, SHP-1 regulates Cbl-b-mediated T cell responses by controlling its tyrosine phosphorylation and ubiquitination.

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“…In vivo, these B cells have impaired induction of tolerance and the mice develop lupus-like autoimmunity (Kitaura et al 2007). A similar enhancement of BCR signaling is observed in B cells deficient in Cbl-b alone (Sohn et al 2003), which affects trafficking of the BCR to late endosomes (Veselits et al 2014). …”

Section: Endocytosis and The Regulation Of Bcr Signalingmentioning

confidence: 86%

“…BCRs that are internalized at a low rate in the absence of antigen are mostly recycled back to the cell surface. However, antigen-induced crosslinking of the BCRs and subsequent signaling increase not only the rate of internalization but also the rate of sorting into late endosomes (Aluvihare et al 1997), which requires ubiquitination of the BCR by c-Cbl (Katkere et al 2012;Zhang et al 2007) and Cbl-b (Veselits et al 2014). As discussed above, the absence of both of these ubiquitin ligases blocks BCR internalization at the plasma membrane.…”

Section: Trafficking Through the Endosomal Pathwaymentioning

confidence: 99%

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Molecular Mechanisms of B Cell Antigen Gathering and Endocytosis

Hoogeboom

Tolar

2015

Current Topics in Microbiology and Immunology

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Generation of high-affinity, protective antibodies requires B cell receptor (BCR) signaling, as well as antigen internalization and presentation to helper T cells. B cell antigen internalization is initiated by antigen capture, either from solution or from immune synapses formed on the surface of antigen-presenting cells, and proceeds via clathrin-dependent endocytosis and intracellular routing to late endosomes. Although the components of this pathway are still being discovered, it has become clear that antigen internalization is actively regulated by BCR signaling at multiple steps and, vice versa, that localization of the BCR along the endocytic pathway modulates signaling. Accordingly, defects in BCR internalization or trafficking contribute to enhanced B cell activation in models of autoimmune diseases and in B cell lymphomas. In this review, we discuss how BCR signaling complexes regulate each of the steps of this endocytic process and why defects along this pathway manifest as hyperactive B cell responses in vivo.

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Recruitment of Cbl-b to B Cell Antigen Receptor Couples Antigen Recognition to Toll-Like Receptor 9 Activation in Late Endosomes

Cited by 16 publications

References 50 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

Protein Tyrosine Phosphatase SHP-1 Modulates T Cell Responses by Controlling Cbl-b Degradation

Molecular Mechanisms of B Cell Antigen Gathering and Endocytosis

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