SEF/IL-17R (SEFIR) is not enough: an extended SEFIR domain is required for il-17RA-mediated signal transduction.
IL-17, the hallmark cytokine of the Th17 population, mediates immunity to extracellular pathogens and promotes autoimmune immunopathology. The signaling mechanisms triggered by the IL-17 receptor (IL-17RA) and related receptors are strikingly different from other cytokine subclasses. Namely, IL-17Rs contain a conserved SEF/IL-17R (SEFIR) subdomain that engages Act1, leading to activation of TRAF6, NF-κB, and other events. Although the SEFIR is critical for signaling, the molecular details of the functional subdomains within IL-17RA remain poorly characterized. Here, we provide a detailed structure-function analysis delineating the C-terminal boundary of the SEFIR-containing region of IL-17RA. We show that functionality of this domain requires a large extension to the previously identified SEFIR motif. In contrast to the SEFIR, this extension is not conserved among IL-17R family members. Surprisingly, Act1 recruitment is not sufficient for downstream signaling activation, whereas ubiquitination of TRAF6 correlates tightly with functional receptors. We further demonstrate that IL-17RA exhibits signaling properties that are nonredundant with other IL-17R family members. Finally, we report that IL-17 signals synergistically with lymphotoxin-α3, using the same signaling motifs within IL-17RA. These studies provide new insight into the structure-function relationships of IL-17RA and reveal distinct signaling differences among IL-17R family members.
Onishi
Reiko M
RM
From the University of Pittsburgh, Department of Medicine, Division of Rheumatology and Clinical Immunology, Pittsburgh, Pennsylvania 15261.
Park
Sangmi J
SJ
From the University of Pittsburgh, Department of Medicine, Division of Rheumatology and Clinical Immunology, Pittsburgh, Pennsylvania 15261.
Hanel
Walter
W
Department of Oral Biology, University at Buffalo, State University of New York, Buffalo, New York 14214.
Ho
Allen W
AW
From the University of Pittsburgh, Department of Medicine, Division of Rheumatology and Clinical Immunology, Pittsburgh, Pennsylvania 15261; Department of Oral Biology, University at Buffalo, State University of New York, Buffalo, New York 14214.
Maitra
Amarnath
A
Department of Oral Biology, University at Buffalo, State University of New York, Buffalo, New York 14214.
Gaffen
Sarah L
SL
From the University of Pittsburgh, Department of Medicine, Division of Rheumatology and Clinical Immunology, Pittsburgh, Pennsylvania 15261; Department of Oral Biology, University at Buffalo, State University of New York, Buffalo, New York 14214. Electronic address: sig65@pitt.edu.
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; C109985:IL17RA protein, human; C491673:Il17ra protein, mouse; D020381:Interleukin-17; D008233:Lymphotoxin-alpha; D016328:NF-kappa B; D053722:Receptors, Interleukin-17; D048029:TNF Receptor-Associated Factor 6; C414202:TRAF3IP2 protein, human; C515963:Traf3ip2 protein, mouse; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins