Abstract
Interleukin-1 (IL-1) family cytokines are key signaling molecules in both the innate and adaptive immune systems, mediating inflammation in response to a wide range of stimuli. The basic mechanism of signal initiation is a stepwise process in which an agonist cytokine binds its cognate receptor. Together, this cytokine-receptor complex recruits an often-common secondary receptor. Intracellularly, the Toll/IL-1 Receptor (TIR) domains of the two receptors are brought into close proximity, initiating an NF-κB signal transduction cascade. Due to the potent inflammatory response invoked by IL-1 family cytokines, several physiological mechanisms exist to inhibit IL-1 family signaling, including antagonist cytokines and decoy receptors. The numerous cytokines and receptors in the IL-1 superfamily are further classified into four subfamilies, dependent on their distinct cognate receptors—the IL-1, IL-33, and IL-36 subfamilies share IL-1RAcP as their secondary receptor, while IL-18 subfamily utilizes a distinct secondary receptor. Here, we describe how structural biology has informed our understanding of IL-1 family cytokine signaling, with a particular focus on molecular mechanisms of signaling complex formation and antagonism at the atomic level, as well as how these findings have advanced therapeutics to treat some chronic inflammatory diseases that are the result of dysregulated IL-1 signaling.
Highlights
During the hunt for the fever-inducing molecule produced by lymphocytes in the second half of the last century, interleukin 1 (IL-1) was discovered [1]
We have a detailed picture of the general mechanisms of signal activation and inhibition in the IL-1 cytokine family, of which we describe key features in more detail
Comparison of their X-ray structures show that IL-38 has an root mean square deviation (RMSD) of 1.23 Å to IL-1 receptor antagonist (IL-1Ra) and 0.96 Å to IL-36Ra
Summary
During the hunt for the fever-inducing molecule produced by lymphocytes in the second half of the last century, interleukin 1 (IL-1) was discovered [1]. All members of the IL-1 family are extremely potent modulators of inflammation Their activities are regulated on several levels, including gene transcription, expression as inactive proforms, secretion and binding at the receptor level. At the receptor level, signaling can be regulated by antagonistic cytokines These bind to the primary receptor yet do not allow the accessory receptor to form the trimeric complex, prohibiting IL-1 signaling (Figure 1E). The β-trefoil consists of six βhairpins and, using the structure of IL-1β by way of example, the naming of the β-sheets starts consecutively from the N-terminus for all IL-1 family cytokines (Figure 2A) While this structural motif is conserved among the cytokines, their sequence identity is low, even for members that bind the same primary receptor. Similar to other cytokines within the IL-1 family, IL-1α is composed of 12 β-strands in a β-trefoil architecture
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