IL-17 receptor-based signaling and implications for disease

Abstract

IL-17 is a highly versatile pro-inflammatory cytokine crucial for a variety of processes, including host defense, tissue repair, the pathogenesis of inflammatory disease and the progression of cancer. In contrast to its profound impact in vivo, IL-17 exhibits surprisingly moderate activity in cell-culture models, which presents a major knowledge gap about the molecular mechanisms of IL-17 signaling. Emerging studies are revealing a new dimension of complexity in the IL-17 pathway that may help explain its potent and diverse in vivo functions. Discoveries of new mRNA stabilizers and receptor-directed mRNA metabolism have provided insights into the means by which IL-17 cooperates functionally with other stimuli in driving inflammation, whether beneficial or destructive. The integration of IL-17 with growth-receptor signaling in specific cell types offers new understanding of the mitogenic effect of IL-17 on tissue repair and cancer. This Review summarizes new developments in IL-17 signaling and their pathophysiological implications.

Figure 1.. Overview of IL-17 signaling functions in vivo.

Figure 2.. Canonical IL-17 signaling pathways

. A) Transcriptional regulation. Upon IL-17 binding to its heterodimeric receptors IL-17RA and IL-17RC, Act1 activates multiple signaling cascades operating through different TRAF proteins. Engagement of TRAF6 results in the activation of NF-κB, C/EBPβ, C/EBPδ, and MAPK pathways. ERK1/2 mediates phosphorylation of C/EBPβ on Thr-188 and CBAD domain of IL-17R is also required for IL-17A-mediated inducible phosphorylation of C/EBPβ on Thr-179 through GSK3β. IL-17 can also induce different feedback regulatory response by inducing/recruiting deubiquitnase enzymes (A20, USP25) or kinases (TBK1). Hsp90 maintains the integrity of Act1 at the protein level. B) Post-transcriptional regulation. IL-17 signaling through the Act1–TRAF2–TRAF5 complex results in the control of mRNA stability/translation of IL-17 target genes through multiple RNA-binding proteins, including mRNA stabilizing factors (Act1, HuR, Arid5a and DDX3X) or destabilizing factors (SF2 and Regnase-1). Mechanistically, in addition to its role as an adaptor, Act1 functions as an RBP by forming several RNPs (as described in C) contributing majorly to the receptor-mediated selectivity of mRNA stabilization and translation in response to IL-17 stimulation. As a feedforward mechanism, IL-17 induces the expression of Arid5a, which counteracts mRNA degradation mediated by Regnase-1 by recognizing similar sequences within the 3′-UTR of IL-17 targeted mRNA. Arid5 and HuR also promote translation of target mRNAs. C) Models of RNPs. IL-17 signaling results in the formation of multiple, compartmentally-distinct RNPs, controlling different steps of mRNA metabolism. Upon IL-17A stimulation, Act1 is phosphorylated by IKKi, followed by their translocation into the nucleus where Act1 binds to a stem-loop structure in the 3’UTR in the target mRNAs (RNP1). The binding of Act1 competes off SF2 from the mRNAs by bringing IKKi to phosphorylate SF2, preventing SF2-mediated mRNA decay. Act1 follows the mRNAs to cytoplasmic granules such as P-bodies (RNP2) inhibiting Dcp1/2-mediated mRNA decapping by employing TBK1 to phosphorylate Dcp1. Moreover, Arid5a can also stabilize different IL-17-target mRNA in the cytoplasm by counteracting the negative effects of Regnase-1. In addition, IL-17 stimulates TBK1/IKKi-mediated phosphorylation of Regnase-1 in an Act1-dependent manner, removing it from target transcripts and preventing the degradation of mRNA. Finally, Act1-mRNAs are shifted to the polysomes to facilitate HuR’s binding to mRNAs (RNP3) for protein translation. Arid5a is also inducibly associated with the eukaryotic translation initiation complex and facilitates the translation of IL-17 target genes (IκBζ and C/EBPβ). Arid5a: AT-Rich Interaction Domain 5A; CBAD:C/EBPβ activation domain; Dcp: Decapping MRNA; DDX3X: DEAD-Box Helicase 3 X-Linked; ERK: extracellular signal related kinase; GSK: glycogen synthase kinase; Hsp90: Heat shock protein 90; HuR: human antigen R, also known as ELVAL1; IKK: inhibitor of kappa B kinase JNK: Janus kinase; PABP: Poly(A)-binding protein; SF2: splicing factor 2; TRAF: TNF receptor associated factor; TAK1: TGF-β activated kinase 1; TBK1: TANK-binding kinase 1; TPL2: Tumor progression locus 2; β-TrCP: beta-transducin repeat containing; USP25: Ubiquitin Specific Peptidase 25

Figure 3.. Noncanonical IL-17 signaling.

A) Integration of IL-17 signaling with EGFR. In Lrig1⁺ stem cells in the skin, IL-17 stimulation leads to the recruitment of EGFR to the IL-17 receptor complex by TRAF4. The close proximity of IL-17R and EGFR allows the adaptor protein Act1 to recruit c-Src for IL-17A–induced EGFR phosphorylation and subsequent activation of MEKK3-MEK5-ERK5 axis. Activation of this axis instigates the Lrig1⁺ cells to produce progenies for wound healing and tumorigenesis. B) IL-17 cross-talk with FGF signaling. In colonic epithelial cells, the IL-17 receptor adaptor Act1 constitutively binds to GRB2, suppressing FGF2-induced ERK1/2 activation. Upon IL-17 stimulation, Act1 is recruited to the IL-17 receptor, releasing GRB2 to associate with guanine nucleotide exchange factor SOS1 for RAS-RAF dependent ERK1/2 activation. The cooperativity between IL-17 and FGF2 plays a crucial role in the repair of damaged colonic epithelium during intestinal inflammation. C) Integration of IL-17A signaling with NOTCH1. In oligodendrocytes progenitor cells (OPCs), IL-17 stimulation induces the interaction between the extracellular domains of IL-17 receptor and Jagged1-bound NOTCH1, facilitating the cleavage of NOTHC1 intracellular domain (NICD1). The released NICD1 forms a complex with Act1 and translocates into the nucleus, promoting the assembly of RBP-J- and MAML-containing transcriptional machinery that mediates the expression of IL-17-induced NOTCH1 target genes for inflammation and cell proliferation. D) Integration of IL-17 signaling with C-type lectin receptor components. In keratinocytes, multiple signaling proteins that functions in C-type lectin receptor pathway have been implicated in IL-17 signaling. Both Syk and CARD14 can form complexes with Act1 and TRAF6 in response to IL-17 stimulation for NFκB activation.