Interleukin‐11 (IL‐11) receptor cleavage by the rhomboid protease RHBDL2 induces IL‐11 trans‐signaling

Koch, Lydia; Kespohl, Birte; Agthe, Maria; Schumertl, Tim; Düsterhöft, Stefan; Lemberg, Marius K.; Lokau, Juliane; Garbers, Christoph

doi:10.1096/fj.202002087r

Cited by 22 publications

(26 citation statements)

References 57 publications

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“…As a positive control, we used the TMD of Spitz, which can be cleaved by RHBDL2 ( Figures 1 B and S1 A) ( Urban and Freeman, 2003 ; Strisovsky et al., 2009 ). Encouragingly, previously identified substrates such as BCAM, cadherins, and Ephrin proteins were among the top hits ( Johnson et al., 2017 ; Battistini et al., 2019 ); the top hit in our screen, IL11RA2, was also recently reported as an RHBDL2 substrate ( Koch et al., 2021 ). Among our strongest validated hits, we found the fourth TMD of all three members of the Orai family of Ca 2+ channels ( Figures 1 A and 1C).…”

Section: Resultsmentioning

confidence: 51%

Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation

Grieve

Yeh

Chang³

et al. 2021

Molecular Cell

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Summary Calcium influx through plasma membrane calcium release-activated calcium (CRAC) channels, which are formed of hexamers of Orai1, is a potent trigger for many important biological processes, most notably in T cell-mediated immunity. Through a bioinformatics-led cell biological screen, we have identified Orai1 as a substrate for the rhomboid intramembrane protease RHBDL2. We show that RHBDL2 prevents stochastic calcium signaling in unstimulated cells through conformational surveillance and cleavage of inappropriately activated Orai1. A conserved disease-linked proline residue is responsible for RHBDL2’s recognizing the active conformation of Orai1, which is required to sharpen switch-like signaling triggered by store-operated calcium entry. Loss of RHBDL2 control of CRAC channel activity causes severe dysregulation of downstream CRAC channel effectors, including transcription factor activation, inflammatory cytokine expression, and T cell activation. We propose that this surveillance function may represent an ancient activity of rhomboid proteases in degrading unwanted signaling proteins.

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Section: Resultsmentioning

confidence: 51%

Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation

Grieve

Yeh

Chang³

et al. 2021

Molecular Cell

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“… 48 Wt ACE2 and all ACE2 constructs were cloned into the pMOWS or pMOWSCMV (additional CMV promotor) backbone with zeocin resistance 41 , 42 via the NEBuilder HiFi DNA assembly master mix (E2621L, NEB, Ipswich, Massachusetts, USA) according to the manufacturer's manual. pcDNA3.1 expression plasmids encoding HA‐tagged mouse RHBDL1, RHBDL2, RHBDL3, and RHBDL4 were used by us previously 49 and originally provided by Dr Matthew Freeman (Sir William Dunn School of Pathology, Oxford, UK). 50 …”

Section: Methodsmentioning

confidence: 99%

The collectrin‐like part of theSARS‐CoV‐1 and ‐2receptorACE2is shed by the metalloproteinasesADAM10andADAM17

et al. 2022

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The transmembrane protease angiotensin converting enzyme 2 (ACE2) is a protective regulator within the renin angiotensin system and additionally represents the cellular receptor for SARS‐CoV. The release of soluble ACE2 (sACE2) from the cell surface is hence believed to be a crucial part of its (patho)physiological functions, as both, ACE2 protease activity and SARS‐CoV binding ability, are transferred from the cell membrane to body fluids. Yet, the molecular sources of sACE2 are still not completely investigated. In this study, we show different sources and prerequisites for the release of sACE2 from the cell membrane. By using inhibitors as well as CRISPR/Cas9‐derived cells, we demonstrated that, in addition to the metalloprotease ADAM17, also ADAM10 is an important novel shedding protease of ACE2. Moreover, we observed that ACE2 can also be released in extracellular vesicles. The degree of either ADAM10‐ or ADAM17‐mediated ACE2 shedding is dependent on stimulatory conditions and on the expression level of the pro‐inflammatory ADAM17 regulator iRhom2. Finally, by using structural analysis and in vitro verification, we determined for the first time that the susceptibility to ADAM10‐ and ADAM17‐mediated shedding is mediated by the collectrin‐like part of ACE2. Overall, our findings give novel insights into sACE2 release by several independent molecular mechanisms.

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“…More recently, a member of the mammalian rhomboid secretases called rhomboid-like 2 (RHBDL2), the best characterized member of the family, was implicated in the cleavage of IL-6R and IL-11R [29,30], which are traditionally considered metalloprotease substrates. Although these findings are confirmed so far only in vitro, they open the possibility for additional regulation of soluble receptor generation through alternative signalling pathways.…”

Section: Generation Of Soluble Receptors Via Proteolytic Cleavagementioning

confidence: 99%

Soluble forms of cytokine and growth factor receptors: mechanisms of generation and modes of action in the regulation of local and systemic inflammation

Kefaloyianni

2022

FEBS Letters

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Cytokine and growth factor receptors are usually transmembrane proteins, but they can also exist in soluble forms, either through cleavage and release of their ligand-binding extracellular domain or through the secretion of a soluble isoform. As an extension of this concept, transmembrane receptors on exosomes released into the circulation may act similarly to circulating soluble receptors. These soluble receptors add to the complexity of cytokine and growth factor signalling: they can function as decoy receptor that compete for ligand binding with their respective membrane-bound forms thereby attenuating signalling, or stabilize their ligands, or activate additional signalling events through interactions with other cell-surface proteins. Their soluble nature allows for a functional role away from the production sites, in remote cell types and organs. Accumulating evidence demonstrates that soluble receptors participate in the regulation and orchestration of various key cellular processes, particularly inflammatory responses. In this review, we will discuss release mechanisms of soluble cytokine and growth factor receptors, their mechanisms of action and strategies for targeting their pathways in disease.

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Interleukin‐11 (IL‐11) receptor cleavage by the rhomboid protease RHBDL2 induces IL‐11 trans‐signaling

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 22 publications

References 57 publications

Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation

Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation

The collectrin‐like part of theSARS‐CoV‐1 and ‐2receptorACE2is shed by the metalloproteinasesADAM10andADAM17

Soluble forms of cytokine and growth factor receptors: mechanisms of generation and modes of action in the regulation of local and systemic inflammation

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