K63-linked polyubiquitination of transcription factor IRF1 is essential for IL-1-induced production of chemokines CXCL10 and CCL5

Abstract

Although interleukin-1 (IL-1) induces expression of interferon regulatory factor 1 (IRF1), its roles in immune and inflammatory responses and mechanisms of activation remain elusive. Here, we show that IRF1 is essential for IL-1-induced expression of chemokines CXCL10 and CCL5 that recruit mononuclear cells into sites of sterile inflammation. Newly synthesized IRF1 acquires K63-linked polyubiquitylation mediated by cellular inhibitor of apoptosis 2 (cIAP2), which is enhanced by the bioactive lipid sphingosine-1 phosphate (S1P). In response to IL-1, cIAP2 and sphingosine kinase 1, the enzyme that generates S1P, form a complex with IRF1, which leads to its activation. Thus, IL-1 triggers a hitherto unknown signaling cascade that controls induction of IRF1-dependent genes important for sterile inflammation.

Reduction in sphingosine kinase 1 influences the susceptibility to dengue virus infection by altering antiviral responses

“…SK1 is also required for LPS stimulation of TLR4-mediated IL-6 production (Pchejetski et al, 2011). More recently, it has been demonstrated that IRF1-mediated IL-1-stimulated production of CXCL10 is reduced by chemical reduction in SK1 or in SK1 2/2 mice (Harikumar et al, 2014). Our gene expression array data also suggest a significant downregulation of IRF1 (twofold) in uninfected SK1 2/2 compared with WT iMEFs (data not shown).…”

“…Our gene expression array data also suggest a significant downregulation of IRF1 (twofold) in uninfected SK1 2/2 compared with WT iMEFs (data not shown). This change in IRF1 remains to be confirmed by RT-PCR but may contribute to the poor induction of CXCL10 in the absence of SK1, as seen in this study and previously suggested (Harikumar et al, 2014). Together this supports a broader role for SK1 as a signalling mediator for pathogen response pathways.…”

“…We further analysed and compared the kinetics of the induction of these genes in iMEFs and 1uMEFs. Our results demonstrated a significant (Harikumar et al, 2014); (2) SK1 promotes NFk B activation (Alvarez et al, 2010;Xia et al, 2002); (3) SK1 inhibits STAT1 phosphoryation (Seo et al, 2011(Seo et al, , 2010; (4) induction of IFN-b mRNA and protein in both WT and SK1 2/2 iMEFs or 1uMEFs, but, remarkably, there was no or poor subsequent induction of the ISGs for viperin, IFIT1 or CXCL10 in either type of SK1 2/2 MEF. Thus, cells lacking SK1 2/2 (both iMEFs and 1uMEFs) are refractory or delayed in the induction of ISGs in response to DENV infection.…”

NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets

“…IFN-regulatory factor 1 (IRF-1) deficiency leads to reduction in antigen-specific autoimmune diseases including collagen-induced arthritis and experimental autoimmune encephalomyelitis (EAE) (29). More recently, Harikumar et al reported that the transcription factor IRF1 is essential for IL-1β-induced production of the chemokines CCL5 and CXCL10 through its formation of a signaling complex with TRAF6, SphK1, and cIAP2 (30). To understand whether this signaling pathway is involved in controlling the production of CCL5 and CXCL10 in pancreatic islets, we isolated islets from NOD mice and analyzed the expression of IRF1, TRAF6, Sph1, and cIAP2 by real-time PCR (Table S1).…”

Cellular and molecular regulation of innate inflammatory responses

“…60,61 The conventional PTMs such as ubiquitination and phosphorylation and unconventional PTMs such as methylation, acetylation and sumoylation target nearly all critical components of PRR signaling, such as receptors, adaptors, enzymes and transcriptional factors to modulate the quality of PRR signals. [62][63][64][65] Taking PTM control of TLR-triggered tumor necrosis factor receptor-associated factor 6 (TRAF6)/NF-κB signaling pathway as an example. Removal of K63-linked polyubiquitination by A20 66 and TRAF family member-associated NF-κB activator (TANK) 67 is shown to modulate TRAF6 activity for inhibition of TLR signaling activation.…”