A20: central gatekeeper in inflammation and immunity

Abstract

Inappropriate functioning of the immune system is linked to immune deficiency, autoimmune disease, and cancer. It is therefore not surprising that intracellular immune signaling pathways are tightly controlled. One of the best studied transcription factors in immune signaling is NF-kappaB, which is activated by multiple receptors and regulates the expression of a wide variety of proteins that control innate and adaptive immunity. A20 is an early NF-kappaB-responsive gene that encodes a ubiquitin-editing protein that is involved in the negative feedback regulation of NF-kappaB signaling. Here, we discuss the mechanism of action of A20 and its role in the regulation of inflammation and immunity.

FIGURE 1.

Overview of different ubiquitinated targets of A20 in NF-κB, IRF, and JNK signaling pathways. Triggering of different receptors leads to the activation and autoubiquitination of specific members of the TRAF family, which also mediate the Lys⁶³ ubiquitination of downstream kinases and other signaling proteins. Known and potential targets for A20-mediated deubiquitination are indicated. For comparison, ubiquitinated targets for CYLD and DUBA are also shown. Lys⁶³ ubiquitin chains are depicted as beads on a string. TCR/BCR, T cell receptor/B cell receptor.

FIGURE 2.

Schematic representation of the structural domains of human A20 involved in its ubiquitin-editing function and interaction with regulatory proteins. The N-terminal OTU domain mediates the deubiquitinating activity of A20 on RIP1, RIP2, TRAF6, and NEMO, whereas the C-terminal zinc finger domain mediates its ubiquitin ligase activity on RIP1. Regions involved in specific protein-protein interactions or post-translational modifications of A20 are also indicated.