Structural and Functional Attributes of the Interleukin-36 Receptor

Yi, Guanghui; Ybe, Joel A.; Saha, Siddhartha Sankar; Caviness, Gary; Raymond, E.; Ganesan, Rajkumar; Mbow, Moustapha; Kao, C. Cheng

doi:10.1074/jbc.m116.723064

Cited by 39 publications

(61 citation statements)

References 30 publications

(36 reference statements)

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“…It has also been demonstrated that disulfide bonds and N‐linked glycosylation in the ectodomain of IL‐36R could affect signaling transduction by regulating protein accumulation and IL‐36R trafficking to the cell surface, respectively. In addition, a single nucleotide gene polymorphism for IL36R , A471T, resulting in a substitution in the TIR domain leads in decreased IL‐36R signaling by reducing the interaction with IL‐1RAcP …”

Section: Il‐36 Expression and Biochemistrymentioning

confidence: 99%

“…In addition, a single nucleotide gene polymorphism for IL36R, A471T, resulting in a substitution in the TIR domain leads in decreased IL-36R signaling by reducing the interaction with IL-1RAcP. 9 The IL-36 cytokines are located within the same gene cluster on human chromosome 2 as the genes for all other IL-1 family cytokines except for IL-18 and IL-33. The IL-36R also lies in the IL-1R family locus on human chromosome 2.…”

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confidence: 99%

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Regulation and function of interleukin‐36 cytokines

Bassoy

Towne

Gabay

2017

Immunological Reviews

158

174

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The interleukin (IL)-36 cytokines include 3 agonists, IL-36α, IL-36β, and IL-36γ that bind to a common receptor composed of IL-36R and IL-1RAcP to stimulate inflammatory responses. IL-36Ra is a natural antagonist that binds to IL-36R, but does not recruit the co-receptor IL-1RAcP and does not stimulate any intracellular responses. The IL-36 cytokines are expressed predominantly by epithelial cells and act on a number of cells including immune cells, epithelial cells, and fibroblasts. Processing of the N-terminus is required for full agonist or antagonist activity for all IL-36 members. The role of IL-36 has been extensively demonstrated in the skin where it can act on keratinocytes and immune cells to induce a robust inflammatory response that has been implicated in psoriatic disorders. Emerging data also suggest a role for this cytokine family in pulmonary and intestinal physiology and pathology.

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Section: Il‐36 Expression and Biochemistrymentioning

confidence: 99%

mentioning

confidence: 99%

Regulation and function of interleukin‐36 cytokines

Bassoy

Towne

Gabay

2017

Immunological Reviews

158

174

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“…Each half of the heterodimer is showing up as single band with a molecular mass of ϳ70 kDa, which is higher than theoretical molecular mass of 63 kDa. Receptors showing higher molecular mass by SDS-PAGE are likely due to glycosylation (12).…”

Section: Figure 2 Sds-page Gels Showing Purified Soluble Forms Of Rementioning

confidence: 99%

“…However, some attempts to measure the first event of IL-36 activation, which is the direct binding of cytokines and IL-36R, have not been successful (1). Furthermore, a recent study shows IL-36R interacts with IL-1RAcP even in the absence of the agonist (12). Knowledge of how IL-36R becomes activated and inhibited is important to understand a potential drug target that has implications in multiple inflammatory diseases including psoriasis.…”

mentioning

confidence: 99%

Quantitative ligand and receptor binding studies reveal the mechanism of interleukin-36 (IL-36) pathway activation

Zhou

Todorović

Kakavas

et al. 2018

Journal of Biological Chemistry

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IL-36 cytokines signal through the IL-36 receptor (IL-36R) and a shared subunit, IL-1RAcP (IL-1 receptor accessory protein). The activation mechanism for the IL-36 pathway is proposed to be similar to that of IL-1 in that an IL-36R agonist (IL-36α, IL-36β, or IL-36γ) forms a binary complex with IL-36R, which then recruits IL-1RAcP. Recent studies have shown that IL-36R interacts with IL-1RAcP even in the absence of an agonist. To elucidate the IL-36 activation mechanism, we considered all possible binding events for IL-36 ligands/receptors and examined these events in direct binding assays. Our results indicated that the agonists bind the IL-36R extracellular domain with micromolar affinity but do not detectably bind IL-1RAcP. Using surface plasmon resonance (SPR), we found that IL-1RAcP also does not bind IL-36R when no agonist is present. In the presence of IL-36α, however, IL-1RAcP bound IL-36R strongly. These results suggested that the main pathway to the IL-36R·IL-36α·IL-1RAcP ternary complex is through the IL-36R·IL-36α binary complex, which recruits IL-1RAcP. We could not measure the binding affinity of IL-36R to IL-1RAcP directly, so we engineered a fragment crystallizable-linked construct to induce IL-36R·IL-1RAcP heterodimerization and predicted the binding affinity during a complete thermodynamic cycle to be 74 μm The SPR analysis also indicated that the IL-36R antagonist IL-36Ra binds IL-36R with higher affinity and a much slower off rate than the IL-36R agonists, shedding light on IL-36 pathway inhibition. Our results reveal the landscape of IL-36 ligand and receptor interactions, improving our understanding of IL-36 pathway activation and inhibition.

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“…HEK293T cells lack IL-1Rrp2, but expresses IL-1RAcp. Transient transfection with a plasmid to express IL-1Rrp2 and reconstitute IL-36R signaling in HEK293T cells [29]. Overexpression of RNF125 in HEK293T cells was found to increase the level of polyubiquitinated IL-1Rrp2 only when the cells were induced with IL-36γ, mimicking the property observed in NCI cells that express endogenous IL-36R (Fig.…”

Section: Recombinant Rnf125 Ubiquitinates Il-1rrp2 In Hek293t Cellsmentioning

confidence: 99%

E3 Ubiquitin Ligase RNF125 Activates Interleukin-36 Receptor Signaling and Contributes to Its Turnover

Saha

Caviness²,

Yi³

et al. 2017

J Innate Immun

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Signaling by the interleukin-36 receptor (IL-36R) is linked to inflammatory diseases such as psoriasis. However, the regulation of IL-36R signaling is poorly understood. Activation of IL-36R signaling in cultured cells results in an increased polyubiquitination of the receptor subunit, IL-1Rrp2. Treatment with deubiquitinases shows that the receptor subunit of IL-36R, IL-1Rrp2, is primarily polyubiquitinated at the K63 position, which is associated with endocytic trafficking and signal transduction. A minor amount of ubiquitination is at the K48 position that is associated with protein degradation. A focused siRNA screen identified RNF125, an E3 ubiquitin ligase, to ubiquitinate IL-1Rrp2 upon activation of IL-36R signaling while not affecting the activated IL-1 receptor. Knockdown of RNF125 decreases signal transduction by the IL-36R. Overexpression of RNF125 in HEK293T cells activates IL-36R signaling and increases the ubiquitination of IL-1Rrp2 and its subsequent turnover. RNF125 can coimmunoprecipitate with the IL-36R, and it traffics with IL-1Rrp2 from the cell surface to lysosomes. Mutations of Lys568 and Lys569 in the C-terminal tail of IL-1Rrp2 decrease ubiquitination by RNF125 and increase the steady-state levels of IL-1Rrp2. These results demonstrate that RNF125 has multiple regulatory roles in the signaling, trafficking, and turnover of the IL-36R.

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Structural and Functional Attributes of the Interleukin-36 Receptor

Cited by 39 publications

References 30 publications

Regulation and function of interleukin‐36 cytokines

Regulation and function of interleukin‐36 cytokines

Quantitative ligand and receptor binding studies reveal the mechanism of interleukin-36 (IL-36) pathway activation

E3 Ubiquitin Ligase RNF125 Activates Interleukin-36 Receptor Signaling and Contributes to Its Turnover

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