Disorders of ubiquitylation: unchained inflammation

Abstract

Ubiquitylation is an essential post-translational modification that regulates intracellular signalling networks by triggering proteasomal substrate degradation, changing the activity of substrates or mediating changes in proteins that interact with substrates. Hundreds of enzymes participate in reversible ubiquitylation of proteins, some acting globally and others targeting specific proteins. Ubiquitylation is essential for innate immune responses, as it facilitates rapid regulation of inflammatory pathways, thereby ensuring sufficient but not excessive responses. A growing number of inborn errors of immunity are attributed to dysregulated ubiquitylation. These genetic disorders exhibit broad clinical manifestations, ranging from susceptibility to infection to autoinflammatory and/or autoimmune features, lymphoproliferation and propensity to malignancy. Many autoinflammatory disorders result from disruption of components of the ubiquitylation machinery and lead to overactivation of innate immune cells. An understanding of the disorders of ubiquitylation in autoinflammatory diseases could enable the development of novel management strategies.

Fig. 1. Mutations affecting the major ubiquitin activating enzyme UBA1 and proteasome subunits result in type I interferon production and inflammation.

Reduction of cytoplasmic ubiquitylation by mutations affecting ubiquitin-like modifier-activating enzyme UBA1 (resulting in vacuoles, E1 activating enzyme, X-linked autoinflammatory somatic (VEXAS) syndrome) or of proteasome activity by mutations affecting particular proteasomal subunits (resulting in proteasome-associated autoinflammatory syndromes (PRAAS)) decreases the efficiency of endoplasmic reticulum (ER)-associated degradation (ERAD). This alteration results in imbalances in cellular proteostasis and accumulation of unfolded and unnecessary proteins, which activate the three different sensors of the unfolded protein response (UPR), PERK, IRE1α and ATF6. Sensor activation initiates signalling cascades that culminate in the production of specific transcription factors (TFs) that mediate upregulation of expression of ERAD components and chaperones as well as type I interferons, which drive the autoinflammation in VEXAS syndrome and PRAAS. Red stars denote proteins affected by mutation. Blue circles denote K48 linked polyubiquitin chains destined for proteasomal degradation.

Fig. 2. Mutations affecting substrate-specific E3 ligases and deubiquitylases lead to dysregulation of immune signalling networks and inflammation.

a | Simplified model of how the linear-ubiquitylation pathway regulates NF-κB and cell-death signalling during responses to immune stimuli. Upon immune stimulation, the linear-ubiquitin assembly complex (LUBAC), which consists of HOIL-1 (haem-oxidized IRP2 ubiquitin ligase 1), HOIP (HOIL-1-interacting protein) and SHARPIN (SHANK-associated RH domain interactor), assembles linear ubiquitin chains on specific substrates. This is counteracted by the linear-ubiquitin-specific deubiquitylase OTULIN, which also reverses autoubiquitylation and thus stabilizes LUBAC in a cell-type-specific manner. Linear ubiquitin chains are recognized and interpreted by dedicated binding proteins that initiate NF-κB or cell-death signalling pathways. One such linear-ubiquitin reader is the hybrid deubiquitylase–E3 ligase enzyme A20. In this model, LUBAC is a ubiquitin ‘writer’, OTULIN is a ubiquitin ‘eraser’ and A20 is a ubiquitin ‘reader’. b | Loss-of-function mutations affecting subunits of the linear-ubiquitin writer LUBAC, the linear-ubiquitin eraser OTULIN and the linear-ubiquitin effector protein A20 result in autoinflammatory diseases. HA20, haploinsufficiency of A20; ORAS, OTULIN-related autoinflammatory syndrome.

Fig. 3. Disorders of ubiquitylation lead to systemic inflammation and have potential for therapeutic intervention.

Mutations that affect enzymes involved in ubiquitylation pathways (indicated here by red stars) can lead to activation of cell death, unfolded protein response and inflammatory pathways that result in inflammatory disease. Therapeutic intervention might be possible at the levels of enzyme-specific activation and inhibition, pathway-specific inhibition and cytokine inhibition. LUBAC, linear-ubiquitin assembly complex; OTULIN, ubiquitin thioesterase otulin; UBA1, ubiquitin-like modifier-activating enzyme 1.