Structural basis of receptor sharing by interleukin 17 cytokines

Ely, Lauren Kate; Fischer, Suzanne; García, K. Christopher

doi:10.1038/ni.1813

Cited by 172 publications

(187 citation statements)

References 49 publications

(76 reference statements)

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“…IL-17A signaling is mediated through IL-17RA and IL-17RC (72,73). We here show that keratinocytes upregulate IL-17RA upon skin injury and thus become a likely target for IL-17A signaling.…”

Section: Figurementioning

confidence: 57%

Dendritic epidermal T cells regulate skin antimicrobial barrier function

MacLeod¹,

Hemmers²,

Garijo³

et al. 2013

J. Clin. Invest.

127

166

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“…IL-17A signaling is mediated through IL-17RA and IL-17RC (72,73). We here show that keratinocytes upregulate IL-17RA upon skin injury and thus become a likely target for IL-17A signaling.…”

Section: Figurementioning

confidence: 57%

Dendritic epidermal T cells regulate skin antimicrobial barrier function

MacLeod¹,

Hemmers²,

Garijo³

et al. 2013

J. Clin. Invest.

127

166

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“…Our data, in conjunction with data derived from Il-17ra 2/2 mice, support the hypothesis that both IL-17RA and IL-17RC chains are required to form the functional receptor for IL-17 ligands. This premise is also further strengthened by the structure of the IL-17F/IL-17RA complex recently solved by Ely et al (22). The asymmetric IL-17RA/IL-17F complex indicates a preference in forming the heterodimeric receptor complex.…”

Section: Discussionmentioning

confidence: 78%

“…FN2 mediates ligand-independent preassembly, and FN1 mediates conformational alteration upon ligand binding (56). Structural studies show that IL-17RA binds to IL-17F in a 1:2 stoichiometry (22). Engagement of IL-17RA or IL-17RC by IL-17A or IL-17F encourages a "preference" for the second receptor binding site to engage a different receptor and thereby to form a heterodimeric receptor complex (22).…”

Section: Discussionmentioning

confidence: 99%

“…Structural studies show that IL-17RA binds to IL-17F in a 1:2 stoichiometry (22). Engagement of IL-17RA or IL-17RC by IL-17A or IL-17F encourages a "preference" for the second receptor binding site to engage a different receptor and thereby to form a heterodimeric receptor complex (22). These data, together with our results, strongly suggest that IL-17A or IL-17F may bind to either IL-17RA or IL-17RC first and that this binding then induces a conformational change that enables the recruitment of second heterodimeric chain into this receptor complex and hence downstream signal transduction.…”

Section: Discussionmentioning

confidence: 99%

“…These differences in binding affinity may partially explain the weaker biological potencies of IL-17F compared with those of IL-17A on many cell types. Second, the structural complex of IL-17F and IL-17RA, recently solved by Ely et al (22), suggests that there is a preference in forming the heterodimeric receptor complex. Finally, our initial characterization of Il-17rc-deficient mice further supports that IL-17RC is indeed required for the functions of IL-17A and IL-17F (23).…”

mentioning

confidence: 99%

See 2 more Smart Citations

IL-17RC Is Required for IL-17A– and IL-17F–Dependent Signaling and the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Hu¹,

Ota²,

Peng³

et al. 2010

The Journal of Immunology

129

116

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It has been suggested that IL-17RC forms a complex with IL-17RA to mediate the functions of IL-17A and IL-17F homodimers as well as IL-17A/F heterodimers. It is still unclear whether IL-17RC is absolutely required for the signaling of IL-17 cytokines in vivo. By using Il-17rc–deficient mice, we show that IL-17RC is essential for the signaling of IL-17A, IL-17F, and IL-17A/F both in vitro and in vivo. IL-17RC does not preassociate with IL-17RA on the cell surface; rather IL-17A can induce the formation of an IL-17RC and IL-17RA complex. This process is not dependent on the intracellular similar expression to fibroblast growth factor genes and IL-17Rs (SEFIR) domain of IL-17RC, but the SEFIR is essential in IL-17A signal transduction. Finally, Il-17rc−/− mice develop much milder disease in an experimental autoimmune encephalomyelitis model, supporting an essential role for IL-17RC in mediating immune-mediated CNS inflammation.

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Interleukins

Meager

Wadhwa

2013

Encyclopedia of Life Sciences

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The interleukins are a major class of biologically active protein mediators, known as cytokines, that following release from activated cells bind to specific cell surface receptors to induce growth and differentiating functions in target cells. Extensive studies into their genes, structures, receptors, signal transduction pathways and activities in experimental cell cultures have provided considerable knowledge leading to their molecular and biological characterisation. Fundamental findings are that they are mostly pleiotropic mediators, that is, act on more than one cell type or at different stages of cellular development, and stimulate multiple activities, especially where acting in combinations of two or more interleukins. Their production as essentially pure recombinant proteins has enabled studies in experimental model systems to determine whether their activities could be of clinical benefit, or harmful. Subsequently, several interleukins and their antagonists have been evaluated for clinical efficacy and safety in clinical studies, and have yielded promising, though not fully effective, therapeutic treatments for patients with cancer and autoinflammatory diseases. In this article, the molecular characteristics of interleukins, their cognate receptors and intracellular signalling pathways, their biological activities and their potential clinical uses are briefly described. Key Concepts: Interleukins are a broad class of biologically active proteins with hormone‐like actions that regulate the development, differentiation and functions of cells of the immune and haematopoietic systems. The activities of interleukins are mediated via cell surface receptors. Binding of interleukins to receptors triggers gene induction via the activation of intracellular signal transduction pathways. Interleukins exhibit complex biological interactions, both among themselves and with other molecular mediators, in vivo . The proinflammatory and immune‐stimulatory activities of interleukins are essential for host defence against pathogens. Interleukins can be ‘two‐edged swords’, being largely beneficial to the host at low concentrations but deleterious and toxic at high concentrations. The biological properties of interleukins have suggested their potential for development as therapeutic drugs (biopharmaceuticals) against infections and chronic diseases, such as cancer, but so far only a few have proved clinically useful. Antibody and receptor antagonists of interleukins are showing promise for the treatment of autoinflammatory and autoimmune diseases, such as irritable bowel disorders and RA.

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Structural basis of receptor sharing by interleukin 17 cytokines

Cited by 172 publications

References 49 publications

Dendritic epidermal T cells regulate skin antimicrobial barrier function

Dendritic epidermal T cells regulate skin antimicrobial barrier function

IL-17RC Is Required for IL-17A– and IL-17F–Dependent Signaling and the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Interleukins

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