E3 ubiquitin ligases and their control of T cell autoreactivity

Abstract

A loss of T cell tolerance underlies the development of most autoimmune diseases. The design of therapeutic strategies to reinstitute immune tolerance, however, is hampered by uncertainty regarding the molecular mechanisms involved in the inactivation of potentially autoreactive T cells. Recently, E3 ubiquitin ligases have been shown to mediate the development of a durable state of unresponsiveness in T cells called clonal anergy. In this review, we will discuss the mechanisms used by E3 ligases to control the activation of T cells and prevent the development of autoimmunity.

Figure 1

Multi-subunit and single-chain E3 ligases that regulate T cell function. (a) Multi-subunit E3 ligases (Skp1-Cullin-F-box (SCF), Cullin-Elongin BC-SOCS/VHL (CBC), and U-box) are anchored by a Cullin scaffold protein and recruit an E2 ubiquitin-conjugating enzyme via a Roc1 or Rbx RING protein (as shown in blue). Substrate specificity is determined by the binding of the target protein (either with or without the carboxyl terminus of Hsc70-interacting protein (CHIP) and Hsc70 containing pre-ubiquitin complex) to a particular F-box (e.g., Skp2), suppressor of cytokine signaling (SOCS), or von Hippel-Lindau (VHL) protein (red), and is mediated by a Skp1 or Elongin BC adapter protein [6,15,29]. (b) Single-chain E3 ligases contain RING or homologous to E6-associated protein carboxyl terminus (HECT) E2 recruitment (blue) and substrate binding (red) domains within one polypeptide [31,50,93]. The question mark on the putative GRAIL target protein indicates that no substrate has yet been identified. C2, Ca²⁺ binding; PA, protease-associated; Pro, proline rich; TKB, tyrosine kinase binding; TM, transmembrane; UBA, ubiquitin-associated; WW, two tryptophan repeat.

Figure 2

Ubiquitination of key signaling in anergic T cells. (a) Il2 gene transactivation in normal T cells. TCR and CD28 signaling cascades synergistically activate phospholipase C (PLC)γ, PKCθ, Vav, and p85, which are responsible for the induction of transcription factors such as nuclear factor of activated T cells (NF-AT), activating protein 1 (AP-1: Fos and Jun), and nuclear factor κB (NFκB) leading to Il2 gene transcription. (b) Sequestration or degradation of signaling intermediates in activated anergic T cells. Upon stimulation of anergic T cells, increased Cbl-b, Itch, and Nedd4 E3 ligase activities antagonize the normal function of the TCR, Vav, and p85, perhaps sequestering them within an endocytic pathway. Additionally, PLCγ and PKCθ appear to be ubiquitinated and degraded within an endosomal/lysosomal compartment during activation.Ub, ubiquitin.