Corrected and Republished from: The COP9 Signalosome Interacts with and Regulates Interferon Regulatory Factor 5 Protein Stability

Abstract

The transcription factor interferon regulatory factor 5 (IRF5) exerts crucial functions in the regulation of host immunity against extracellular pathogens, DNA damage-induced apoptosis, death receptor signaling, and macrophage polarization. Tight regulation of IRF5 is thus warranted for an efficient response to extracellular stressors and for limiting autoimmune and inflammatory responses. Here we report that the COP9 signalosome (CSN), a general modulator of diverse cellular and developmental processes, associates constitutively with IRF5 and promotes its protein stability. The constitutive CSN/IRF5 interaction was identified using proteomics and confirmed by endogenous immunoprecipitations. The CSN/IRF5 interaction occurred on the carboxyl and amino termini of IRF5; a single internal deletion (Δ455-466) was found to significantly reduce IRF5 protein stability. CSN3 was identified as a direct interacting partner of IRF5, and knockdown of this subunit with small interfering RNAs (siRNAs) resulted in enhanced degradation. Degradation was further augmented by knockdown of CSN1 and CSN3 together. The ubiquitin E1 inhibitor UBEI-41 or the proteasome inhibitor MG132 prevented IRF5 degradation, supporting that its stability is regulated by the ubiquitin-proteasome system. Importantly, activation of IRF5 by the death receptor ligand tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resulted in enhanced degradation via loss of the CSN/IRF5 interaction. This study defines the CSN as a new interacting partner of IRF5 that controls its stability. KEYWORDS COP9, IRF5T he interferon regulatory factor (IRF) family consists of nine cellular IRFs, each with pleiotropic biological functions (1). IRF5 has an important role in the induction of type I interferons (IFNs) and proinflammatory cytokines and is thus a critical mediator of innate and adaptive immunity (2-4). More recent studies have shown that Irf5 is an autoimmune susceptibility gene associated with increased risk of Citation Korczeniewska J, Barnes BJ. 2018. Corrected and republished from: The COP9 signalosome interacts with and regulates interferon regulatory factor 5 protein stability.

Advances and challenges in targeting IRF5, a key regulator of inflammation

“…Another study demonstrated a role for IRF5 in induction of IFN‐β following fungal infection by the pathogen Candida albicans , whereby the C‐type lectin receptor Dectin‐1 activation of IRF5 was dependent on the tyrosine kinase Syk and the adaptor protein Card9 . An alternative model suggests that the COP9 signalosome (CSN) interacts with and stabilizes IRF5 . Stimulation of the death receptor by TRAIL ligand leads to phosphorylation of the complex by an unknown kinase and IRF5 degradation through a ubiquitin–proteasome pathway.…”

“…Thus, binding sites on IRF5 could be a potential peptide target and would require identifying the peptide sequences that are crucial for the IRF5–protein interactions. Another IRF5‐binding partner that has been shown to interact with and stabilize IRF5 is the CSN, which is thought to protect IRF5 from degradation by the ubiquitin–proteasome pathway . This interaction was mapped to the carboxyl and amino termini of IRF5.…”

Pathogen Effectors: Exploiting the Promiscuity of Plant Signaling Hubs

“…In-house gene ontology (GO) enrichment analyses (of 210 genes with GO annotations) indicate that 24% of the effector hubs are related to defense responses, 30% to the regulation of gene expression, and 35% to primary metabolic processes. In addition, parallels to mammalian effector hubs can be observed, as exemplified by the CSN5A protein, which is part of the COP9 signalosome and is essential in regulating innate immune responses across eukaryotes (Table 1) [36,37].…”