Ubiquitin Makes Its Mark on Immune Regulation

Abstract

Ubiquitination, the covalent attachment of ubiquitin molecules to proteins, is emerging as a widely utilized mechanism for rapidly regulating cell signaling. Recent studies indicate that ubiquitination plays potent roles in regulating a variety of signals in both innate and adaptive immune cells. Here, we will review recent studies of ubiquitin ligases, ubiquitin chain linkages and ubiquitin binding proteins that highlight the diversity and specificity of ubiquitin dependent functions in immune cells. We will also review studies that shed light on how ubiquitination signals are integrated in cell-type specific fashion to regulate the immune system in vivo.

The E3 Ubiquitin Ligase Neuregulin Receptor Degradation Protein 1 (Nrdp1) Promotes M2 Macrophage Polarization by Ubiquitinating and Activating Transcription Factor CCAAT/Enhancer-binding Protein β (C/EBPβ)

“…Recently, ubiquitination has been demonstrated in many aspects of the immunological functions, ranging from innate immune responses, antigen presentation, T cell activation, and tolerance to immune defense (7,8). The ubiquitin system includes ubiquitin and enzymes like E1-activating enzyme, E2-conjugating enzyme, and E3 ubiquitin ligase (9).…”

“…E3 ubiquitin ligase determines substrate specificity and facilitates transfer of the ubiquitin to lysine on substrate proteins, many of which have been identified in immune responses (10,11). It has been known that polyubiquitin chains linked through lysine 48 of ubiquitin (Lys-48-linked polyubiquitination) always marks substrates for proteasome-dependent degradation (8). For instance, Lys-48-linked polyubiquitination of IB-␣ is essential for its degradation and the following activation of NF-B (12).…”

Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β

“…Ubiquitination occurs predominantly via K48 or K63 linkages and consists of the addition of a single ubiquitin (monoubiquitination) or the assembly of ubiquitin of various lengths that are assembled by the successive attachment of ubiquitin to lysines of previously conjugated ubiquitin (polyubiquitination) (34). Although ubiquitin contains seven lysine residues that have been shown to mediate ubiquitin conjugation, K48 and K63 linkages are the best studied.…”

Itch expression by Treg cells controls Th2 inflammatory responses

“…The posttranslational modification mediated by ubiquitin conjugation is one of the key regulatory mechanisms that control innate or adaptive immune responses (23,24). Ubiquitin conjugation to a protein substrate involves a cascade of enzymatic reactions including IL-4, E2, and E3 enzymes (25).…”