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 toward 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 from amino acids 455 to 466 (⌬455-466) was found to significantly reduce IRF5 protein stability. CSN subunit 3 (CSN3) was identified as a direct interacting partner of IRF5, and knockdown of this subunit with small interfering RNAs 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 the idea that its stability is regulated by the ubiquitin-proteasome system. Importantly, activation of IRF5 by the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resulted in enhanced degradation via loss of the CSN/IRF5 interaction. This study defines CSN to be a new interacting partner of IRF5 that controls its stability.

Interferon Regulatory Factor 5 (IRF5) Interacts with the Translation Initiation Complex and Promotes mRNA Translation During the Integrated Stress Response to Amino Acid Deprivation

“…The eIF3 complex is responsible for 40S ribosomal recruitment and is a structure homologous to the COP9 signalosome (CSN) (58). Interestingly, an interaction between IRF5 and CSN was described in a previous report (59). Our findings may indicate that IRF5 possesses affinity for structures bearing similarity to CSN (e.g.…”

Low‐grade inflammatory polarization of monocytes impairs wound healing

“…Our data further support the notion that super-low-dose LPS programmes monocytes into an IRF-5 + low-grade inflammatory state. Since IRF-5 protein is known to be modulated by degradation [33], and lysosome function is among the key mechanisms modulating protein degradation [34], we investigated whether super-low-dose LPS may enhance IRF-5 stability through disrupting lysosome function. Western TUDCA (500 μM) was added to some cultures and the cells were then stained with anti-LAMP1 and anti-LCIII antibodies after starvation; the fusion of lysosomes with autophagosomes was visualized by confocal microscopy; data represent three experiments blotting indicated that treatment with the lysosome inhibitor chloroquine increased IRF-5 protein levels in cultured monocytes, suggesting that disruption of lysosome function may account for the enhanced IRF-5 protein stability ( Figure 5A).…”

HIV-2 Vpx Protein Interacts with Interferon Regulatory Factor 5 (IRF5) and Inhibits Its Function

“…Recently, the COP9 signalosome has been shown to interact with and stabilize IRF5. The complex formation with COP9 signalosome subunits prevents IRF5 from being degraded through a ubiquitin-proteasome pathway (64). The binding of Vpx to IRF5 may hinder or disrupt the association of IRF5 with COP9 signalosome subunits and therefore destabilize IRF5, which could result in decreased transcriptional activity of IRF5.…”