SOCS2-Induced Proteasome-Dependent TRAF6 Degradation: A Common Anti-Inflammatory Pathway for Control of Innate Immune Responses

Abstract

Pattern recognition receptors and receptors for pro-inflammatory cytokines provide critical signals to drive the development of protective immunity to infection. Therefore, counter-regulatory pathways are required to ensure that overwhelming inflammation harm host tissues. Previously, we showed that lipoxins modulate immune response during infection, restraining inflammation during infectious diseases in an Aryl hydrocarbon receptor (AhR)/suppressors of cytokine signaling (SOCS)2-dependent-manner. Recently, Indoleamine-pyrrole 2,3- dioxygenase (IDO)-derived tryptophan metabolites, including L-kynurenine, were also shown to be involved in several counter-regulatory mechanisms. Herein, we addressed whether the intracellular molecular events induced by lipoxins mediating control of innate immune signaling are part of a common regulatory pathway also shared by L-kynurenine exposure. We demonstrate that Tumor necrosis factor receptor-associated factor (TRAF)6 – member of a family of adapter molecules that couple the TNF receptor and interleukin-1 receptor/Toll-like receptor families to intracellular signaling events essential for the development of immune responses – is targeted by both lipoxins and L-kynurenine via an AhR/SOCS2-dependent pathway. Furthermore, we show that LXA4- and L-kynurenine-induced AhR activation, its subsequent nuclear translocation, leading SOCS2 expression and TRAF6 Lys47-linked poly-ubiquitination and proteosome-mediated degradation of the adapter proteins. The in vitro consequences of such molecular interactions included inhibition of TLR- and cytokine receptor-driven signal transduction and cytokine production. Subsequently, in vivo proteosome inhibition led to unresponsiveness to lipoxins, as well as to uncontrolled pro-inflammatory reactions and elevated mortality during toxoplasmosis. In summary, our results establish proteasome degradation of TRAF6 as a key molecular target for the anti-inflammatory pathway triggered by lipoxins and L-kynurenine, critical counter-regulatory mediators in the innate and adaptive immune systems.

System-wide Analysis of the T Cell Response

“…Public T-cell clones express TCR sequence motifs shared by different individuals, and are often expanded by immunization, infection, or autoimmunity (McBerry et al, 2012; Venturi et al, 2008). To study the role of public repertoires in zebrafish, we defined a public sequence as one appearing in at least two different individuals, as previously defined in other studies (Li et al, 2012).…”

“…Because of these limitations, it is still unclear what fraction of the potential T-cell repertoire is expressed, and how similar are the repertories of different individuals in the quiescent state and during the course of an immune response. In addition, TCR sequences shared by different individuals (termed public TCR sequences) are detected in all vertebrates in multiple biological contexts, a surprising finding when the number of potential unique CDR3 sequences generated by VDJ recombination is considered (McBerry et al, 2012; Venturi et al, 2008). However, the significance of public TCRs on the repertoire, as well as their response to stimulation is unknown.…”

Identification of Cytokinin-Responsive Genes Using Microarray Meta-Analysis and RNA-Seq in Arabidopsis

“…Another set of interesting genes identified encodes TNF-receptor associated factor (TRAF)-like proteins (AT5G26290, AT3G20370, AT5G26260, AT5G52330, and AT1G582700), identified by both microarray metaanalysis and RNA-seq. The TRAF-like genes are a large gene family in Arabidopsis encoding potential E3 ligase proteins (Huang et al, 2004;Gingerich et al, 2007;McBerry et al, 2012), only a very few of which have been functionally characterized. These genes may play a role in the regulation of protein turnover in response to cytokinin.…”

Lipoxin A4 inhibits lipopolysaccharide-induced production of inflammatory cytokines in keratinocytes by up-regulating SOCS2 and down-regulating TRAF6

“…However, preincubation with LXA4, to some extent, inhibited the TRAF6 synthesis induced by LPS in NHEKs. Some studies demonstrated that LXA4-induced AhR activation and its subsequent nuclear translocation lead to SOCS2 expression, TRAF6 Lys47-linked poly-ubiquitination and proteosome-mediated degradation of the adapter proteins [17] . It was also reported that LXA4, signaling through ALXR and AhR, mediates innate and acquired immune responses via induced expression of SOCS2 [8] .…”

“…McBerry et al recently reported that TRAF6 is degraded by both LXA4 and L-kynurenine via an SOCS2-dependent pathway [17] . Our hypothesis is that whether SOCS2/TRAF6 are involved in the anti-inflammation process of LXA4 in keratinocytes.…”