Ubiquitin enzymes in the regulation of immune responses

Abstract

Ubiquitination plays a central role in the regulation of various biological functions including immune responses. Ubiquitination is induced by a cascade of enzymatic reactions by E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme, and E3 ubiquitin ligase, and reversed by deubiquitinases. Depending on the enzymes, specific linkage types of ubiquitin chains are generated or hydrolyzed. Because different linkage types of ubiquitin chains control the fate of the substrate, understanding the regulatory mechanisms of ubiquitin enzymes is central. In this review, we highlight the most recent knowledge of ubiquitination in the immune signaling cascades including the T cell and B cell signaling cascades as well as the TNF signaling cascade regulated by various ubiquitin enzymes. Furthermore, we highlight the TRIM ubiquitin ligase family as one of the examples of critical E3 ubiquitin ligases in the regulation of immune responses.

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

“…PTMs alter the functionality of targeted proteins in the cell by regulating the activity, stability, cellular compartmentalization, conformation and future interactions with additional factors. Rapidly altering and expanding the capabilities of cellular factors confers the ability to respond to countless environmental stimuli including pathogen sensing and immune responses [5,11,12]. One of the most widely used and ubiquitous forms of PTMs is protein ubiquitination [13].…”

“…Ubiquitin is a 76 amino acid (aa) protein and is able to interact with targets through covalent bonds (anchored ubiquitin) or non-covalent associations (unanchored ubiquitin) [4,5,14].…”

“…In the final stage, interaction between the E2 and one of over 600 E3 ubiquitin-ligating enzymes allows for the transfer of ubiquitin from the E2 onto the target protein ( Fig. 2) [4,5,15,17]. The E2 and E3 enzymes can be expressed in a tissue-or cell-type-specific manner, and this may also depend on stimulus, including virus infection.…”

“…Formation of polyubiquitin is made possible by covalent interactions between the C-terminal Gly of one ubiquitin and one of seven Lys residues on another ubiquitin (K6-, K11-, K27-, K29-, K33-, K48-and K63-linked polyubiquitin). Alternatively, the C-terminal Gly of one ubiquitin can covalently bind the N-terminal methionine (Met) of another ubiquitin to form 'linear' polyubiquitin (M1-linked polyubiquitin) [4,5,11,17]. Furthermore, the ubiquitin machinery is capable of synthesizing polyubiquitin chains that are not covalently bound to a substrate (unanchored polyubiquitin).…”

“…1). Although we focus on current developments within the tripartite motif (TRIM) field, other excellent reviews that focus more on the antiviral aspects of TRIMs and that highlight older studies are also available [2][3][4][5][6][7][8][9][10].…”