Recycling and Reshaping—E3 Ligases and DUBs in the Initiation of T Cell Receptor-Mediated Signaling and Response

Abstract

T cell activation plays a central role in supporting and shaping the immune response. The induction of a functional adaptive immune response requires the control of signaling processes downstream of the T cell receptor (TCR). In this regard, protein phosphorylation and dephosphorylation have been extensively studied. In the past decades, further checkpoints of activation have been identified. These are E3 ligases catalyzing the transfer of ubiquitin or ubiquitin-like proteins to protein substrates, as well as specific peptidases to counteract this reaction, such as deubiquitinating enzymes (DUBs). These posttranslational modifications can critically influence protein interactions by targeting proteins for degradation by proteasomes or mediating the complex formation required for active TCR signaling. Thus, the basic aspects of T cell development and differentiation are controlled by defining, e.g., the threshold of activation in positive and negative selection in the thymus. Furthermore, an emerging role of ubiquitination in peripheral T cell tolerance has been described. Changes in the function and abundance of certain E3 ligases or DUBs involved in T cell homeostasis are associated with the development of autoimmune diseases. This review summarizes the current knowledge of E3 enzymes and their target proteins regulating T cell signaling processes and discusses new approaches for therapeutic intervention.

Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy

“…Indeed, the ubiquitin–proteasome system (UPS) regulates the degradation of misfolded and aggregated proteins as well as protein turnover [ 14 ]. It is now widely accepted that ubiquitination also plays a key role in the control of several fundamental biological processes, including the cell cycle [ 15 ], apoptosis [ 16 ], autophagy [ 11 , 14 ], epigenetics [ 17 ], as well as NF-kB and T-cell receptor signaling [ 18 , 19 , 20 , 21 ], and DNA repair and transcription [ 22 , 23 , 24 ], to name a few. Similarly, deubiquitinases modulate diverse cellular events, including the cell cycle [ 25 ], apoptosis [ 26 ], receptor signaling [ 16 , 21 ], gene transcription [ 24 ] and DNA repair pathways [ 23 ].…”

“…It is now widely accepted that ubiquitination also plays a key role in the control of several fundamental biological processes, including the cell cycle [ 15 ], apoptosis [ 16 ], autophagy [ 11 , 14 ], epigenetics [ 17 ], as well as NF-kB and T-cell receptor signaling [ 18 , 19 , 20 , 21 ], and DNA repair and transcription [ 22 , 23 , 24 ], to name a few. Similarly, deubiquitinases modulate diverse cellular events, including the cell cycle [ 25 ], apoptosis [ 26 ], receptor signaling [ 16 , 21 ], gene transcription [ 24 ] and DNA repair pathways [ 23 ]. The ubiquitination system is also conserved throughout evolution and modulates a wide range of biological functions in bacteria and viruses, where it is emerging as a major player in the bacterial pathogenic mechanisms of infectious diseases [ 27 , 28 , 29 , 30 , 31 , 32 ].…”