Two N-Linked Glycans Differentially Control Maturation, Trafficking and Proteolysis, but not Activity of the IL-11 Receptor

“…Similar to IL-6R, the ectodomain of IL-11R is subjected to N-linked glycosylation. However, in contrast to IL-6R, glycosylation at Asn-194 seems to be essential for the transport to the plasma membrane and substitution of Asn-194 with alanine resulted in predominant localization to the ER ( Agthe et al, 2018b ).…”

Section: The Life-cycle Of Il-6 Family Receptor Complexesmentioning

confidence: 99%

Endosomes as Signaling Platforms for IL-6 Family Cytokine Receptors

Schmidt-Arras

Rose–John

2021

Front. Cell Dev. Biol.

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Interleukin-6 (IL-6) is the name-giving cytokine of a family of eleven members, including IL-6, CNTF, LIF, and IL-27. IL-6 was first recognized as a B-cell stimulating factor but we now know that the cytokine plays a pivotal role in the orchestration of inflammatory processes as well as in inflammation associated cancer. Moreover, IL-6 is involved in metabolic regulation and it has been shown to be involved in major neural activities such as neuroprotection, which can help to repair and to reduce brain damage. Receptor complexes of all members formed at the plasma membrane contain one or two molecules of the signaling receptor subunit GP130 and the mechanisms of signal transduction are well understood. IL-6 type cytokines can also signal from endomembranes, in particular the endosome, and situations have been reported in which endocytosis of receptor complexes are a prerequisite of intracellular signaling. Moreover, pathogenic GP130 variants were shown to interfere with spatial activation of downstream signals. We here summarize the molecular mechanisms underlying spatial regulation of IL-6 family cytokine signaling and discuss its relevance for pathogenic processes.

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“…Nglycosylation is initiated in the ER, and the sugar chains are then further processed in the Golgi. Therefore, the fully matured IL-11R at the plasma membrane has a higher molecular weight compared to intermediates still located in intracellular organelles [36,38]. Additionally, the ER has an important role in terms of quality control, as it retains not correctly folded proteins and prevents their onward transportation to the Golgi.…”

Section: Introductionmentioning

confidence: 99%

“…After translation, the IL‐11R is transported through the endoplasmic reticulum (ER) and the Golgi apparatus before being inserted into the plasma membrane. The amino‐acid sequence of the IL‐11R contains two sequons for N ‐linked glycosylation at the two asparagine residues N127 and N194 [38]. N ‐glycosylation is initiated in the ER, and the sugar chains are then further processed in the Golgi.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of the craniosynostosis‐associated interleukin‐11 receptor variants p.T306_S308dup and p.E364_V368del

Kespohl,

Hegele,

Düsterhöft

et al. 2023

The FEBS Journal

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Interleukin‐11 (IL‐11) is a member of the IL‐6 family of cytokines and is an important factor for bone homeostasis. IL‐11 binds to and signals via the membrane‐bound IL‐11 receptor (IL‐11R, classic signaling) or soluble forms of the IL‐11R (sIL‐11R, trans‐signaling). Mutations in the IL11RA gene, which encodes the IL‐11R, are associated with craniosynostosis, a human condition in which one or several of the sutures close prematurely, resulting in malformation of the skull. The biological mechanisms of how mutations within the IL‐11R are linked to craniosynostosis are mostly unexplored. In this study, we analyze two variants of the IL‐11R described in craniosynostosis patients: p.T306_S308dup, which results in a duplication of three amino‐acid residues within the membrane‐proximal fibronectin type III domain, and p.E364_V368del, which results in a deletion of five amino‐acid residues in the so‐called stalk region adjacent to the plasma membrane. The stalk region connects the three extracellular domains to the transmembrane and intracellular region of the IL‐11R and contains cleavage sites for different proteases that generate sIL‐11R variants. Using a combination of bioinformatics and different biochemical, molecular, and cell biology methods, we show that the IL‐11R‐T306_S308dup variant does not mature correctly, is intracellularly retained, and does not reach the cell surface. In contrast, the IL‐11R‐E364_V368del variant is fully biologically active and processed normally by proteases, thus allowing classic and trans‐signaling of IL‐11. Our results provide evidence that mutations within the IL11RA gene may not be causative for craniosynostosis and suggest that other regulatory mechanism(s) are involved but remain to be identified.

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Two N-Linked Glycans Differentially Control Maturation, Trafficking and Proteolysis, but not Activity of the IL-11 Receptor

Cited by 10 publications

References 47 publications

Mutations in Craniosynostosis Patients Cause Defective Interleukin-11 Receptor Maturation and Drive Craniosynostosis-like Disease in Mice

Mutations in Craniosynostosis Patients Cause Defective Interleukin-11 Receptor Maturation and Drive Craniosynostosis-like Disease in Mice

Endosomes as Signaling Platforms for IL-6 Family Cytokine Receptors

Molecular characterization of the craniosynostosis‐associated interleukin‐11 receptor variants p.T306_S308dup and p.E364_V368del

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