Regulation of the innate immune system by ubiquitin and ubiquitin-like modifiers

Abstract

Detection of invading pathogens by pattern recognition receptors (PRRs) is crucial for the activation of the innate immune response. These sensors signal through intertwining signaling cascades which result in the expression of pro-inflammatory cytokines and type I interferons. Conjugation, or binding, of ubiquitin and ubiquitin-like modifiers (UBLs) to a plethora of immune signaling molecules forms a common theme in innate immune regulation. Numerous E3 ligases and deubiquitylating enzymes (DUBs) actively modify signaling components in order to achieve a balanced activation of the innate immune system. This review will discuss how this balance is achieved and which questions remain regarding innate immune regulation by ubiquitin and UBLs.

Fig. 1

Overview of innate immunity and ubiquitylation. (A) Infection triggers the activation of the innate immune signaling. Insufficient activation leads to uncontrolled infection, but hyper-immunity is detrimental to the host. A balanced activation of the innate immune signaling, at least partly regulated by UBLs, is required for pathogen clearance and host survival. (B) The innate immune response is a swift response, which is required for control of the initial infection and activation of the adaptive immune response. (C and D) Conjugation of UBLs involves sequential activity of three classes of enzymes, E1-activating enzymes, E2-conjugases and E3-ligases. DUBs remove conjugated UBLs from substrates. The functions of different ubiquitin chain linkages are listed with corresponding references, as well as the general functions of the other UBLs.

Fig. 2

PRR signaling pathways and their regulation by ubiquitin. PRR signaling pathways are heavily regulated by UBLs. Basic components of the pathways are shown here, more detailed sub-pathways are depicted in Fig. 3. PRRs are shown in blue, adaptor proteins in yellow, the most important E3 ligases in green, kinases in orange and transcription factors in purple. Other E3 ligases and DUBs that influence PRR signaling are listed along with their chain specificity or UBL and effect (+ or −) on the outcome of the signaling cascade.

Fig. 3

Ubiquitin-mediated regulation of RIG-I, TAK1 and TBK1/IKKɛ. (A) Viral 5′-triphosphate RNA is recognized by RIG-I, which leads to a conformational change and then multimerization for downstream signaling (top part). Activation of RIG-I signaling is regulated by several distinct ubiquitylation mechanisms. (B) The TAK1 complex can be activated by K63 chains (bound or free) from a variety of inputs as listed. Once the TAB2 and TAB3 subunits bind K63 chains, TAK1 auto-phosphorylates and initiates downstream signaling. (A–C) Activating E3 ligases are shown in green, deactivating in red and DUBs in light blue. For more detailed descriptions the reader is referred to the text.