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Cbl- and Nedd4-family ubiquitin ligases: balancing tolerance and immunity.

ABSTRACT: Engagement of the T cell receptor (TCR) with its cognate peptide/MHC initiates a cascade of signaling events that results in T cell activation. Limiting the extent and duration of TCR signaling ensures a tightly constrained response, protecting cells from the deleterious impact of chronic activation. In order to limit the duration of activation, T cells must adjust levels of key signaling proteins. This can be accomplished by altering protein synthesis or by changing the rate of protein degradation. Ubiquitination is a process of 'tagging' a protein with ubiquitin and is one means of initiating protein degradation. This process is activated when an E3 ubiquitin ligase mediates the transfer of ubiquitin to a target protein. Accordingly, E3 ubiquitin ligases have recently emerged as key regulators of immune cell function. This review will explore how a small group of E3 ubiquitin ligases regulate T cell responses and thus direct adaptive immunity.

SUBMITTER: Gay DL

PROVIDER: S-EPMC3901516 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Cbl- and Nedd4-family ubiquitin ligases: balancing tolerance and immunity.

Gay Denise L DL Ramón Hilda H Oliver Paula M PM

Immunologic research 20080101 1-3

Engagement of the T cell receptor (TCR) with its cognate peptide/MHC initiates a cascade of signaling events that results in T cell activation. Limiting the extent and duration of TCR signaling ensures a tightly constrained response, protecting cells from the deleterious impact of chronic activation. In order to limit the duration of activation, T cells must adjust levels of key signaling proteins. This can be accomplished by altering protein synthesis or by changing the rate of protein degradat ...[more]

PMID: 18827983

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Project description:The complement of fungal cell surface proteins is widely regulated by ubiquitination of membrane proteins, which results in their endocytosis and vacuolar degradation. For diverse fungal transporters, the specificity of ubiquitination is conferred by alpha arrestin adaptors, which recruit the Nedd4 family E3 ubiquitin ligase Rsp5. A recent study showed that one mammalian alpha arrestin also mediates ubiquitination and lysosomal trafficking of an activated plasma membrane receptor. Here we first screen all five widely-expressed human alpha arrestins for subcellular localization in ligand-stimulated and -unstimulated cells overexpressing the seven transmembrane receptor vasopressin 2. We then characterize the effects of alpha arrestins ARRDC3 and ARRDC4 upon activation of the seven transmembrane receptors vasopressin 2 and beta adrenergic 2. Using biochemical and imaging approaches, we show that ligand-activated receptors interact with alpha arrestins, and this results in recruitment of Nedd4 family E3 ubiquitin ligases and receptor ubiquitination - which are known to result in lysosomal trafficking. Our time course studies show these effects occur in the first 1-5 minutes after ligand activation, the same time that beta arrestins are known to have roles in receptor endocytic trafficking and kinase signaling. We tested the possibility that alpha and beta arrestins function coordinately and found co-immunoprecipitation and colocalization evidence to support this. Others recently reported that Arrdc3 knockout mice are lean and resistant to obesity. In the course of breeding our own Arrdc3-deficient mice, we observed two novel phenotypes in homozygotes: skin abnormalities, and embryonic lethality on normal chow diet, but not on high fat diet. Our findings suggest that alpha and beta arrestins function coordinately to maintain the optimal complement and function of cell surface proteins according to cellular physiological context and external signals. We discuss the implications of the alpha arrestin functions in fungi having evolved into coordinated alpha/beta arrestin functions in animals.

Dataset Information

Cbl- and Nedd4-family ubiquitin ligases: balancing tolerance and immunity.

Publications

Cbl- and Nedd4-family ubiquitin ligases: balancing tolerance and immunity.

Similar Datasets

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