Dataset Information

A highly conserved luminal ER exit motif in the pseudoproteases iRhom1 and iRhom2 is indispensable for TNF�� and EGF receptor ligand release

ABSTRACT: Membrane-tethered signalling proteins such as TNF�� and many EGF receptor ligands undergo shedding by the metalloproteinase ADAM17 to get released. The pseudoproteases iRhom1 and iRhom2 are important for the ER exit and activity of ADAM17. Yet, their structural requirements to promote ER exit remained unexplored. Utilising in silico and in vitro methods, we here map the conserved iRhom homology domain (IRHD) and provide insights into its structure and function. We identified a highly conserved motif within the IRHD, which is indispensable for the ER exit of iRhoms and termed it CERES (conserved ER exit sequence). Strikingly, single point mutations in CERES abrogate the ER exit without disrupting other iRhom functions. We confirmed the physiological significance of CERES by inactivating it in mice which abrogates ADAM17-mediated shedding ex vivo and in vivo. This demonstrates a crucial role of CERES in the ADAM17-dependent release of various growth factor and cytokine signals.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Epithelial Cell

SUBMITTER: Christian Preisinger

LAB HEAD: Stefan D��sterh��ft

PROVIDER: PXD016948 | Pride | 2021-05-25

REPOSITORIES: Pride

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Publications

The iRhom homology domain is indispensable for ADAM17-mediated TNFα and EGF receptor ligand release.

Düsterhöft Stefan S Kahveci-Türköz Selcan S Wozniak Justyna J Seifert Anke A Kasparek Petr P Ohm Henrike H Liu Shixin S Kopkanova Jana J Lokau Juliane J Garbers Christoph C Preisinger Christian C Sedlacek Radislav R Freeman Matthew M Ludwig Andreas A

Cellular and molecular life sciences : CMLS 20210505 11

Membrane-tethered signalling proteins such as TNFα and many EGF receptor ligands undergo shedding by the metalloproteinase ADAM17 to get released. The pseudoproteases iRhom1 and iRhom2 are important for the transport, maturation and activity of ADAM17. Yet, the structural and functional requirements to promote the transport of the iRhom-ADAM17 complex have not yet been thoroughly investigated. Utilising in silico and in vitro methods, we here map the conserved iRhom homology domain (IRHD) and pr ...[more]

PMID: 33950315

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Project description: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-cre 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 inhibit adipocyte differentiation and 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, and 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 modulates energy balance in adipocytes by inhibiting adipocyte differentiation, thermogenesis and lipid catabolism.

Dataset Information

A highly conserved luminal ER exit motif in the pseudoproteases iRhom1 and iRhom2 is indispensable for TNF������ and EGF receptor ligand release

Publications

The iRhom homology domain is indispensable for ADAM17-mediated TNFα and EGF receptor ligand release.

Similar Datasets

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A highly conserved luminal ER exit motif in the pseudoproteases iRhom1 and iRhom2 is indispensable for TNF�� and EGF receptor ligand release