The Ubiquitin-Proteasome System in Immune Cells

Abstract

The ubiquitin-proteasome system (UPS) is the major intracellular and non-lysosomal protein degradation system. Thanks to its unique capacity of eliminating old, damaged, misfolded, and/or regulatory proteins in a highly specific manner, the UPS is virtually involved in almost all aspects of eukaryotic life. The critical importance of the UPS is particularly visible in immune cells which undergo a rapid and profound functional remodelling upon pathogen recognition. Innate and/or adaptive immune activation is indeed characterized by a number of substantial changes impacting various cellular processes including protein homeostasis, signal transduction, cell proliferation, and antigen processing which are all tightly regulated by the UPS. In this review, we summarize and discuss recent progress in our understanding of the molecular mechanisms by which the UPS contributes to the generation of an adequate immune response. In this regard, we also discuss the consequences of UPS dysfunction and its role in the pathogenesis of recently described immune disorders including cancer and auto-inflammatory diseases.

Keywords: autoinflammation; cancer; immunity; proteostasis; ubiquitin–proteasome system.

Figure 1

Ubiquitin conjugation pathway of protein substrates and their subsequent degradation by proteasome complexes. Ubiquitin activation requires its transfer to an E1 ubiquitin-activating enzyme under ATP hydrolysis. In a second step, the activated ubiquitin is transferred to an E2 ubiquitin-conjugating enzyme and used for the covalent modification of intracellular proteins with the support of E3 ubiquitin ligases. Protein substrates may be marked with one single ubiquitin molecule on one acceptor site resulting in mono-ubiquitination. The ubiquitin molecule may also be subjected to ubiquitination, thereby leading to the formation of various polyubiquitin chains, among which the K48-linkages represent the most prevalent proteasome-targeting signals. Major proteasome complexes include standard proteasomes (SP), immunoproteasomes (IP), and hybrid proteasomes (HP) which distinguish themselves by the nature of their catalytic subunits and/or regulators (19S, 11S). It is understood that both IP and HP exhibit a higher capacity of degrading ubiquitin-modified proteins than SP.

Figure 2

Key contributions of the UPS to the regulation of the NF-κB signaling pathway in response to LPS. Depicted is the NF-B pathway emanating from the cell surface receptor TLR4 upon LPS binding. NF-κB signalling relies on the upstream E3 ubiquitin ligase TRAF6 which catalyzes K63-linked polyubiquitin chains which themselves activate the TAK kinase complex. Activated TAK1 phosphorylates the downstream heterotrimeric IKK kinase complex whose full activation further requires the generation of Met1-linked linear polyubiquitin chains by LUBAC. Once activated, IKK promotes the phosphorylation of κBα and its subsequent proteasomal degradation following its K48-ubiquitination by SCF^TRCP, thereby allowing NF-κB nuclear translocation. Genes induced by NF-κB include those coding for deubiquitinating enzymes Otulin and A20 which ensure a negative feedback loop by trimming linear and K63-polyubiquitin chains.

Figure 3

Regulation of the IRF3 signaling pathway by the UPS following LPS exposure. Binding of PAMP to intracellular PRR results in the autoactivation of the E3 ubiquitin ligase TRAF3 which activates the downstream TBK1/IKK1ε kinase complex by generating K63-linked polyubiquitin chains. The TBK1/IKK1ε complex catalyzes the phosphorylation of IRF3, thereby inducing its nuclear translocation and the transcription of genes coding for type I IFN. A prolonged activation of TBK1/IKK1ε by TRAF3 is prevented by the E3 ubiquitin ligases DTX4, TRIP, and TRIM27 which modify TBK1/IKK1ε with K48-linked polyubiquitin chains and target it for proteasomal degradation. Negative feedback mechanisms also include the upregulation of the CYLD and TRIM21 proteins which remove K63-linkages and target IRF3 for proteasomal degradation, respectively.

Figure 4

The UPS plays a central role in alerting and resolving imbalances of protein homeostasis. Proteostasis disruption is typically characterized by the accumulation of misfolded and/or damaged proteins in the ER lumen which fail to be retro-translocated to the cytosol by ERAD for proteasomal degradation. Protein aggregation in the ER is sensed by the three ER receptors IRE1α, ATF6, and PERK which then undergo activation to trigger the UPR. This ultimately results in the activation of transcription factors ATF6, sXBP1, and ATF4, thereby promoting the transcription of genes coding for proteins destined to compensate the burden of unfolded/damaged proteins. Perturbed protein homeostasis is also sensed in the cytosol by GCN2 and PKR which undergo autoactivation following amino acid deficiency and stress granules, respectively. Both of these kinases phosphorylate eIF2α, thereby intersecting with the PERK-mediated pathway of the UPR.