Ubiquitination-mediated regulation of interferon responses - PubMed (original) (raw)

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Ubiquitination-mediated regulation of interferon responses

Serge Y Fuchs. Growth Factors. 2012 Jun.

Abstract

Interferon cytokine family members shape the immune response to protect the host from both pathologic infections and tumorigenesis. To mediate their physiologic function, interferons evoke a robust and complex signal transduction pathway that leads to the induction of interferon-stimulated genes with both proinflammatory and antiviral functions. Numerous mechanisms exist to tightly regulate the extent and duration of these cellular responses. Among such mechanisms, the post-translational conjugation of ubiquitin polypeptides to protein mediators of interferon signaling has emerged as a crucially important mode of control. In this mini-review, we highlight recent advances in our understanding of these ubiquitin-mediated mechanisms, their exploitation by invading viruses, and their possible utilization for medical intervention.

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Figures

Figure 1

Figure 1. IFN signaling and the regulatory role of ubiquitination

Upon engaging a cognate receptor complex (IFNAR1-IFNAR2 for Type 1 IFN, IFNGR1-IFNGR2 for Type 2 IFN or IL28RA-IL10R2 for Type 3 IFN) IFN activate receptor-associated JAKs. A resulting tyrosine phosphorylation of STAT proteins leads to the formation of transcriptionally active complexes (STAT1 homodimers for all types and additional STAT1-STAT2-IRF9 complexes for Types 1/3 IFN) and ensuing induction of ISGs. Cellular (β-Trcp, SOCS, SLIM) and diverse viral E3 ubiquitin ligases facilitate the ubiquitination of various mediators of IFN signaling pathway to limit the extent and duration of this signaling.

Figure 2

Figure 2. A hypothetical mechanism for ubiquitination-mediated stimulation of IFNAR1 internalization

Sequence alignment of membrane-adjacent proximal fragments of the cytoplasmic tail of IFNAR1 is shown on the left. Tyr-based endocytic motif YXXΨ, where Ψ is a hydrophobic residue, is shown in bold letters. Proline residues conferring the IFNAR1 tail turns are marked by green letters. Figure also shows an unstimulated receptor whose endocytic motif does not interact with endocytic machinery (e.g., AP50 protein) due to spatial interference by associated TYK2. Upon ligand binding and ensuing ubiquitination, a putative conformational change can allow the recognition of the endocytic motif and subsequent internalization. We speculate that formation of two different types of polyubiquitin chains (Lys48- versus Lys63-linked) oriented toward plasma membrane at different angles may stabilize the conformation conducive for endocytosis.

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