Reply to “The binding stoichiometry of CIN85 SH3 domain A and Cbl-b”

Jozic, Daniela; Cárdenes, Nayra; Deribe, Yonathan Lissanu; Moncalián, Gabriel; Hoeller, Daniela; Groemping, Yvonne; Đikić, Ivan; Rittinger, Katrin; Bravo, Jerónimo

doi:10.1038/nsmb0908-891

Cited by 3 publications

(4 citation statements)

References 7 publications

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“…Using ITC, we determined a 2 : 1 stoichiometry for CIN85-SH3A with the Cbl-b peptide, indicating formation of a trimeric structure in solution, consisting of a Cbl-b peptide sandwiched by two CIN85-SH3A domains, as shown in the crystal structure. Previous studies reported that formation of the heterotrimer was due to a crystallization artifact and disputed the formation of such complex in solution [9,10,12]. In our work, we have resolved the supposed controversy as the existence of a trimeric complex is in agreement with our results from ITC, NMR and the ab initio reconstructed shape obtained from analysis of the SAXS curves.…”

Section: Atypical Polyproline Recognition: the Role Of Arginine Residsupporting

confidence: 87%

“…Cbl‐b/c‐Cbl was shown to simultaneously contact two N‐terminal CIN85/CMS SH3 domains, providing additional molecular functions to the ubiquitin ligase . The stoichiometry of the complexes formed has been controversial for Cbl and CIN85‐SH3A . Using several complementary biophysical techniques, we aimed to fully characterize the interactions established by the family of adaptors, including both the CIN85 and CD2AP N‐terminal SH3 domains (SH3A), with two cellular ligands, Cbl‐b and CD2.…”

Section: Discussionmentioning

confidence: 99%

“…The crystal structure of the CMS N‐terminal SH3A domain (which shares 100% sequence identity with the SH3A domain of CD2AP) in complex with a CD2‐derived peptide also suggested formation of heterotrimers, providing a conserved feature in the molecular mechanism of cluster formation involving the CIN85/CMS family of adaptor proteins . However, these findings were later disputed because no evidence was observed for the existence of a heterotrimer between CIN85 and Cbl‐b in solution , although the experimental conditions were not directly comparable .…”

Section: Introductionmentioning

confidence: 99%

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Multimeric and differential binding of CIN85/CD2AP with two atypical proline‐rich sequences from CD2 and Cbl‐b*

et al. 2013

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The CD2AP (CD2-associated protein) and CIN85 (Cbl-interacting protein of 85 kDa) adaptor proteins each employ three Src homology 3 (SH3) domains to cluster protein partners and ensure efficient signal transduction and down-regulation of tyrosine kinase receptors. Using NMR, isothermal titration calorimetry and small-angle X-ray scattering methods, we have characterized several binding modes of the N-terminal SH3 domain (SH3A) of CD2AP and CIN85 with two natural atypical proline-rich regions in CD2 (cluster of differentiation 2) and Cbl-b (Casitas B-lineage lymphoma), and compared these data with previous studies and published crystal structures. Our experiments show that the CD2AP-SH3A domain forms a type II dimer with CD2 and both type I and type II dimeric complexes with Cbl-b. Like CD2AP, the CIN85-SH3A domain forms a type II complex with CD2, but a trimeric complex with Cbl-b, whereby the type I and II interactions take place at the same time. Together, these results explain how multiple interactions among similar SH3 domains and ligands produce a high degree of diversity in tyrosine kinase, cell adhesion or T-cell signaling pathways. Abbreviations Cbl, Casitas B-lineage lymphoma; CD2AP, CD2-associated protein; CD2, cluster of differentiation 2; CIN85, Cbl-interacting protein of 85 kDa; CMS, Cas ligand with multiple SH3 domains; SH3 domain, Src homology 3 domain.

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Section: Atypical Polyproline Recognition: the Role Of Arginine Residsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multimeric and differential binding of CIN85/CD2AP with two atypical proline‐rich sequences from CD2 and Cbl‐b*

et al. 2013

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“…The first is elongation factor 1␦, a subunit of the EF-1 complex, which mediates the elongation of peptide chains during translation of mRNAs. The second is the adaptor protein CIN85, a partner of the E3 ubiquitin ligase Cbl, which ubiquitinates various cell surface receptors and initiates their internalization, endocytic trafficking, and sorting (5,6,(9)(10)(11)(12)(13)(14). Subsequently, it was observed that ICP0 alone, in the absence of other viral proteins, induced a reduction in the surface abundance of epidermal growth factor receptor (EGFR) and decreased the total amount of EGFR in the cells due to internalization and subsequent degradation of the receptor in endocytic compartments (6).…”

mentioning

confidence: 99%

Cbl E3 Ligase Mediates the Removal of Nectin-1 from the Surface of Herpes Simplex Virus 1-Infected Cells

Deschamps

Dogrammatzis

Mullick

et al. 2017

J Virol

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The Cbl E3 ligase has been linked to the down-modulation of surface signaling responses by inducing internalization of surface receptors. The adaptor protein CIN85 is a partner of Cbl that augments many of these interactions. Previously, an interaction was demonstrated between ICP0 and CIN85, which results in the removal of epidermal growth factor receptor (EGFR) from the surface of the infected cells with a concomitant attenuation of EGFR signaling. Here, we examined whether Cbl mediates the removal of the herpes simplex virus 1 (HSV-1) entry receptor Nectin-1 from the surface of infected cells. We found the following: (i) that Cbl, Nectin-1, and the viral glycoprotein D (gD) form a complex in infected cells; (ii) that during infection Nectin-1 is removed from the surface of the infected cells but is retained on the surface of cells that have been depleted of Cbl; and (iii) that in cells infected with a ΔICP0 mutant virus, Nectin-1 remained on the cell surface. Thus, Cbl is necessary but not sufficient for the removal of Nectin-1 from the cell surface. In addition, we observed that in Cbl-depleted cells there was enhanced entry after infection. These cells were susceptible to secondary infections by HSV-1. Viral entry in CIN85-depleted cells was only moderately enhanced compared to that in the Cbldepleted cells, suggesting that the Cbl-Nectin-1 interaction is likely the key to the downregulation of surface Nectin-1. The removal of the HSV-1 entry receptor Nectin-1 from the surface of the infected cells may be part of the strategy of the virus to efficiently spread to uninfected cells. IMPORTANCEThe Cbl E3 ligase suppresses surface signaling responses by inducing internalization of surface components. The targets of Cbl include such components as immune system receptors, growth factor receptors, adhesion, and cell-to-cell contact molecules. The immediate early protein ICP0 of herpes simplex virus 1 (HSV-1) interacts with CIN85, an adaptor protein that augments Cbl functions. The consequence of this interaction is the removal of the epidermal growth factor receptor (EGFR) from the surface of the infected cells with concomitant suppression of the EGF ligand signaling. The viral entry receptor Nectin-1 is also internalized during HSV-1 infection in a Cbl-dependent mechanism, and that increases the opportunity of the virus to spread to uninfected cells. The diversion of the Cbl/CIN85 endocytic machinery may be a strategy utilized by the virus to alter the cell surface pattern to prevent detrimental host responses.KEYWORDS Cbl E3 ligase, Nectin-1, endocytosis, ICP0, HSV-1, cell surface D uring herpes simplex virus 1 (HSV-1) infection, the immediate early protein ICP0 (infected cell protein 0) exerts two major sets of functions. First, ICP0 localizes in the nucleus immediately after its production and is involved in the blockage of the gene silencing machinery and provides an impediment to certain branches of innate immunity (1-4). After ICP0 accomplishes its major nuclear functions, it translocates to

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Effects on exocytosis by two HSV-1 mutants unable to block autophagy

Waisner,

Lasnier,

Suma

et al. 2023

J Virol

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Herpes simplex virus 1 (HSV-1) is a prominent human pathogen that manipulates host responses to support the infection. HSV-1 infection triggers an increased release of extracellular vesicles (EVs) through the CD63 biogenesis pathway that contains the DNA sensor STING and exerts an antiviral effect on recipient cells. However, it is currently unknown how different viral proteins influence EV production. The viral proteins ICP0 and ICP34.5 are important for blocking host responses, including autophagy. Considering that autophagy and exocytosis are interwoven processes regulating intercellular communication, we sought to determine changes in EV biogenesis after infection with a ΔICP0 and a ΔICP34.5 virus that displayed defects in blocking autophagy compared with wild-type virus. ΔICP34.5 virus induced a greater release of EVs as compared to HSV-1(F), whereas ΔICP0 virus did not. EVs released by ΔICP34.5-infected cells differ in origin from those released by HSV-1(F)-infected cells as they contained markers of microvesicles and apoptotic bodies, but lacked major tetraspanins (CD63 or CD81) or lysosomal membrane proteins. EVs released by ΔICP0-infected cells are generated through the CD63 biogenesis pathway activated by HSV-1(F) but displayed reduced amounts of cargo. EVs released by these mutant viruses triggered robust innate immunity gene expression in uninfected recipient cells that exceeded host responses due to infection by these viruses. Overall, we have characterized how infection with viruses unable to block autophagy affects EV biogenesis, and their effect on recipient cells. IMPORTANCE Pathogens often hijack extracellular vesicle (EV) biogenesis pathways for assembly, egress, and cell-to-cell spread. Herpes simplex virus 1 (HSV-1) infection stimulated EV biogenesis through a CD63 tetraspanin biogenesis pathway and these EVs activated antiviral responses in recipient cells restricting the infection. HSV-1 inhibits autophagy to evade the host, and increased CD63 exocytosis could be a coping mechanism, as CD63 is involved in both cargo delivery to lysosomes during autophagy and exocytosis. We analyzed exocytosis after infection with two HSV-1 mutants, a ΔICP34.5 and a ΔICP0, that could not inhibit autophagy. Unlike HSV-1(F), neither of these viruses stimulated increased EV biogenesis through the CD63 pathway. ΔICP34.5 stimulated production of microvesicles and apoptotic bodies that were CD63-negative, while ΔICP0 displayed an overall reduced production of EVs. These EVs activated innate immunity gene expression in recipient cells. Given the potential use of these mutants for therapeutic purposes, the immunomodulatory properties of EVs associated with them may be beneficial.

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Reply to “The binding stoichiometry of CIN85 SH3 domain A and Cbl-b”

Cited by 3 publications

References 7 publications

Multimeric and differential binding of CIN85/CD2AP with two atypical proline‐rich sequences from CD2 and Cbl‐b*

Multimeric and differential binding of CIN85/CD2AP with two atypical proline‐rich sequences from CD2 and Cbl‐b*

Cbl E3 Ligase Mediates the Removal of Nectin-1 from the Surface of Herpes Simplex Virus 1-Infected Cells

Effects on exocytosis by two HSV-1 mutants unable to block autophagy

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