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.

Fig. 1

Ubiquitin-mediated protein conjugation. Ubiquitination is the enzymatic process of conjugating ubiquitin, 8 kDa protein, to a target protein. This process involves a highly regulated series of enzymatic reactions. The E3 ubiquitin ligases are the crucial components that provide specificity to the process through direct interaction with the substrate, or target protein. Ubiquitination can result in, among other things, target degradation

Fig. 2

Cbl-family domain structure. Members of the Cbl-family of RING-type E3 ubiquitin ligases share certain modular features. The N-terminus has a PTB (a.k.a TKB) for interaction with tyrosine phosphorylated proteins and receptor tyrosine kinases. The zinc-finger containing RING domain binds an ubiquitin-loaded E2 enzyme. The polyproline-rich region is a protein–protein interacting domain that has been shown to interact with both adaptor proteins and targets. The C-terminus UBA domain typically bind ubiquitinated proteins but can also facilitate hetero- and homo-dimerization. Domain organization of these murine proteins is based on the National Center for Biotechnology Information database (http://www.ncbi.nlm.nih.gov/)

Fig. 3

Nedd4-family domain structure. Members of the mouse Nedd4-family of E3 ubiquitin ligases share structural features. Domains of Nedd4-family members include the C2 domain, two-fourth WW domains, and the HECT domain. The HECT-domain is the catalytic subunit of the protein. Domain organization of these murine proteins is based on the National Center for Biotechnology Information database (http://www.ncbi.nlm.nih.gov/)

Fig. 4

Cbl-family targets in T cell activation. Following T cell activation, Cbl E3 ligases ubiquitinate subunits of the TCR as well as phosphorylated signaling components including ZAP70, the p85 subunit of PI3Kinase, Fyn, Lck and Vav [–, –78]. This ubiquitination results in dampening of T cell activation signals. P, phosphorylation; Ca⁺⁺, calcium ions

Fig. 5

Model of how Itch, Nedd4, and Cbl-b E3 ubiquitin ligases regulate T cell activation