The pseudoprotease iRhom1 controls ectodomain shedding of membrane proteins in the nervous system

Tüshaus, Johanna; Müller, Stephan; Shrouder, Joshua; Arends, Martina; Simons, Mikael; Plesnila, Nikolaus; Blobel, Carl P.; Lichtenthaler, Stefan F.

doi:10.1096/fj.202100936r

Cited by 10 publications

(8 citation statements)

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“…This approach carries the advantage that cells can be grown under normal serum-containing conditions [93]. As shown in Figure 5A-B , after filtering for potentially shed proteins[65] (see Materials and Methods), we observed a significant reduction in the levels of the cleaved form of a transmembrane protein called Semaphorin 4B (Sema4B) in the secretome from the KO inguinal and brown primary adipocytes ( Fig 5A-B ). Semaphorins are secreted, transmembrane and cell-surface-attached proteins that signal mainly by interaction with Plexin receptors, and act on axonal guidance, and regulate morphology and motility of many cell types [94].…”

Section: Resultsmentioning

confidence: 99%

“…Proteins were considered sufficiently expressed if detectable in at least 4 of the 5 samples per treatment condition. To enrich for candidate membrane proteins shed by metalloprotease activity we focused on proteins that have a single transmembrane helix or a glycosylphosphatidylinositol (GPI) anchor, as previously described[65]. A p-value ≤ 0.05 was used as cut-off for significantly and differentially shed proteins.…”

Section: Methodsmentioning

confidence: 99%

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Semaphorin 4B is an ADAM17-cleaved inhibitor of adipocyte thermogenesis

Amin

Badenes

Tueshaus

et al. 2022

Preprint

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Objective: The metalloprotease ADAM17 (also called TACE) plays fundamental roles in homeostasis by shedding key signaling molecules from the cell surface. Although its importance for the immune system and epithelial tissues is well-documented, little is known about the role of ADAM17 in metabolic homeostasis. The purpose of this study was to determine the impact of ADAM17 expression, specifically in adipose tissues, on metabolic homeostasis. Methods: We used histopathology, molecular, proteomic, transcriptomic, in vivo integrative physiological and ex vivo biochemical approaches to determine the impact of adipose tissue-specific deletion of ADAM17 upon adipocyte and whole organism metabolic physiology. Results: ADAM17adipoq-creΔ/Δ mice exhibited a hypermetabolic phenotype characterized by elevated energy consumption and increased levels of adipocyte thermogenic gene expression. On a high fat diet, these mice were more thermogenic, while exhibiting elevated expression levels of genes associated with lipid oxidation and lipolysis. This hypermetabolic phenotype protected mutant mice from obesogenic challenge, limiting weight gain, hepatosteatosis and insulin resistance. Activation of beta-adrenoceptors by the neurotransmitter norepinephrine, a key regulator of adipocyte physiology, triggered the shedding of ADAM17 substrates, and regulated ADAM17 expression at the mRNA and protein levels, hence identifying a functional connection between thermogenic licensing and the regulation of ADAM17. Proteomic studies identified Semaphorin 4B (SEMA4B), as a novel ADAM17-shed adipokine, whose expression is regulated by physiological thermogenic cues that acts to dampen thermogenic responses in adipocytes. Transcriptomic data showed that cleaved SEMA4B acts in an autocrine manner in brown adipocytes to dampen the expression of genes involved in thermogenesis, adipogenesis, lipid uptake, storage and catabolism. Conclusion: Our findings identify a novel ADAM17-dependent axis, regulated by beta-adrenoceptors and mediated by the ADAM17-cleaved form of SEMA4B, that may act to limit uncontrolled energy depletion during thermogenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Semaphorin 4B is an ADAM17-cleaved inhibitor of adipocyte thermogenesis

Amin

Badenes

Tueshaus

et al. 2022

Preprint

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“…This is similar to other membrane proteins, such as APP, that are mainly shed by one protease, but may additionally be shed by other proteases, often to a smaller extent [ 26 ]. However, sgp130 was not significantly changed in the serum of hypomorphic ADAM17 knock-out mice [ 71 ] or in the conditioned medium of neurons lacking ADAM10 or active ADAM17 [ 65 , 87 ] or in CSF of mice lacking active ADAM17 [ 87 ]. Generation of antibodies specifically binding the C-terminus of the spliced or the BACE1-cleaved sgp130 may help to set up assays that distinguish the proteolytically generated and the differentially spliced sgp130 forms.…”

Section: Discussionmentioning

confidence: 99%

The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130

Müller

Shmueli

Feng

et al. 2023

Mol Neurodegeneration

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Background The protease BACE1 is a major drug target for Alzheimer’s disease, but chronic BACE1 inhibition is associated with non-progressive cognitive worsening that may be caused by modulation of unknown physiological BACE1 substrates. Methods To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. Results Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as an in vivo BACE1 substrate. Gp130 was also reduced in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. Mechanistically, we demonstrate that BACE1 directly cleaves gp130, thereby attenuating membrane-bound gp130 and increasing soluble gp130 abundance and controlling gp130 function in neuronal IL-6 signaling and neuronal survival upon growth-factor withdrawal. Conclusion BACE1 is a new modulator of gp130 function. The BACE1-cleaved, soluble gp130 may serve as a pharmacodynamic BACE1 activity marker to reduce the occurrence of side effects of chronic BACE1 inhibition in humans. Graphical abstract

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“…Mammals encode two iRhom paralogs with partially redundant roles in ADAM17 regulation at the organismal and cellular levels ( Christova et al, 2013 ; Li et al, 2015 ). iRhom1 regulates ADAM17 shedding in the nervous system ( Sun et al, 2021 ; Tüshaus et al, 2021 ) and in endothelial cells ( Babendreyer et al, 2020 ). iRhom2 KOs develop normally but fail to secrete TNF, a key ADAM17 substrate that coordinates the responses to infection and chronic inflammatory diseases; loss of iRhom2 attenuates the development of multiple inflammatory diseases in mouse models ( Adrain et al, 2012 ; McIlwain et al, 2012 ; Siggs et al, 2012 ; Issuree et al, 2013 ; Luo et al, 2016 ; Barnette et al, 2018 ; Chaohui et al, 2018 ; Qing et al, 2018 ; Sundaram et al, 2019 ; Adrain & Cavadas, 2020 ; Kim et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

The ADAM17 sheddase complex regulator iTAP/Frmd8 modulates inflammation and tumor growth

et al. 2023

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The metalloprotease ADAM17 is a sheddase of key molecules, including TNF and epidermal growth factor receptor ligands. ADAM17 exists within an assemblage, the “sheddase complex,” containing a rhomboid pseudoprotease (iRhom1 or iRhom2). iRhoms control multiple aspects of ADAM17 biology. The FERM domain–containing protein iTAP/Frmd8 is an iRhom-binding protein that prevents the precocious shunting of ADAM17 and iRhom2 to lysosomes and their consequent degradation. As pathophysiological role(s) of iTAP/Frmd8 have not been addressed, we characterized the impact of iTAP/Frmd8 loss on ADAM17-associated phenotypes in mice. We show that iTAP/Frmd8 KO mice exhibit defects in inflammatory and intestinal epithelial barrier repair functions, but not the collateral defects associated with global ADAM17 loss. Furthermore, we show that iTAP/Frmd8 regulates cancer cell growth in a cell-autonomous manner and by modulating the tumor microenvironment. Our work suggests that pharmacological intervention at the level of iTAP/Frmd8 may be beneficial to target ADAM17 activity in specific compartments during chronic inflammatory diseases or cancer, while avoiding the collateral impact on the vital functions associated with the widespread inhibition of ADAM17.

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The pseudoprotease iRhom1 controls ectodomain shedding of membrane proteins in the nervous system

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 10 publications

References 87 publications

Semaphorin 4B is an ADAM17-cleaved inhibitor of adipocyte thermogenesis

Semaphorin 4B is an ADAM17-cleaved inhibitor of adipocyte thermogenesis

The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130

The ADAM17 sheddase complex regulator iTAP/Frmd8 modulates inflammation and tumor growth

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