Ubiquitination-mediated regulation of interferon responses

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 anti-viral function. 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.

Hope and Fear for Interferon: The Receptor-Centric Outlook on the Future of Interferon Therapy

“…This ubiquitination occurs on many ubiquitin acceptors within the cytoplasmic tail of IFNAR1. However, the polyubiquitination of a specific cluster of lysine residues (such as K501, 525, and 526 within human IFNAR1) appears to be critical others 2004, 2007a;Fuchs 2012). This ubiquitin transfer to either K48-linked or K63-linked polyubiquitin chains on these lysines is likely to involve 2 diverse E2 ubiquitinconjugating enzymes: Cdc34 and Ubc13/Uev1 (our unpublished data).…”

“…This pathway constitutes an important and specific mechanism for restricting the extent and duration of IFN-a signaling (Stark and others 1998;Coccia and others 2006). Endocytosed IFNAR2 demonstrates a propensity to recycle back to the cell surface (Marijanovic and others 2007), whereas endocytosis of IFNAR1 usually leads to its degradation [reviewed in and Fuchs (2012)]. As endocytosis of the entire receptor is often determined by an assortment of mechanisms accelerating endocytosis and degradation of IFNAR1 (Kumar and others 2003;Uze and others 2007), most of this review will be dedicated to discussing these mechanisms.…”

“…As a result, this cell is rendered nearly insensitive to the subsequent exposure to IFN. Color images available online at www.liebertpub.com/jir Fuchs, 2012). This process is expected to be counteracted by specific deubiquitinating enzymes, whose nature and mode of function will be determined by future studies.…”

Type I Interferon Controls Propagation of Long Interspersed Element-1

“…These cytokines act by interacting with the Type 1 IFN receptor that consists of IFNAR1 and IFNAR2 chains and mediates all cellular effects of IFN (2)(3)(4). Association of IFN with a heteromeric receptor leads to activation of Janus kinases TYK2 and JAK1 and phosphorylation-dependent activation of the Signal Transducers and Activators of Transcription (STAT1/2) proteins.…”

“…Association of IFN with a heteromeric receptor leads to activation of Janus kinases TYK2 and JAK1 and phosphorylation-dependent activation of the Signal Transducers and Activators of Transcription (STAT1/2) proteins. These proteins interact with IRF9 to form a potent transcription factor that up-regulates the expression of several hundreds of IFNstimulated genes, whose products both elicit anti-viral effects and contribute to the development of the inflammatory tissue injury (2,3,(5)(6)(7)(8). Since integration of viruses into host DNA induces genetic changes (9), it may be hypothesized that antiviral cytokines including IFN can also play a role in maintaining the integrity of the host genome.…”