Proteomics

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


ABSTRACT: Proteolytic ectodomain shedding of membrane proteins is a fundamental mechanism to control the communication between cells and their environment. A key protease for membrane protein shedding is ADAM17, which requires a non-proteolytic subunit, either inactive Rhomboid 1 (iRhom1) or iRhom2 for its activity. While iRhom1 and iRhom2 are coexpressed in most tissues and appear to have largely redundant functions, the brain is an organ with predominant expression of iRhom1. Yet, little is known about the spatio-temporal expression of iRhom1 in mammalian brain and about its function in controlling membrane protein shedding in the nervous system. Here, we demonstrate that iRhom1 is expressed in mouse brain from the prenatal stage to adulthood with a peak in early postnatal development. In the adult mouse brain iRhom1 was widely expressed, including in cortex, hippocampus, olfactory bulb and cerebellum. Proteomic analysis of the secretome of primary neurons and of cerebrospinal fluid (CSF), obtained from iRhom1-deficient and control mice, identified several membrane proteins that require iRhom1 for their shedding in vitro or in vivo. One of these proteins was the ‘multiple-EGF-like-domains protein 10’ (MEGF10), a phagocytic receptor in the brain that is linked to the removal of amyloid and apoptotic neurons. MEGF10 was further validated as an ADAM17 substrate using ADAM17-deficient mouse embryonic fibroblasts. Taken together, this study discovers a role for iRhom1 in controlling membrane protein shedding in the mouse brain, establishes MEGF10 as an iRhom1-dependent ADAM17 substrate and demonstrates that iRhom1 is widely expressed in murine brain.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cerebrospinal Fluid, Primary Neuron

SUBMITTER: Stephan Mueller  

LAB HEAD: Stefan F. Lichtenthaler

PROVIDER: PXD028096 | Pride | 2021-10-07

REPOSITORIES: Pride

Dataset's files

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Action DRS
20200622_114518_iSPECS_neuron_iR1KO_DIA_Mouseo_...__.sne.zip Other
JT_002_CSF_07.raw Raw
JT_002_CSF_45.raw Raw
JT_002_CSF_46.raw Raw
JT_002_CSF_48.raw Raw
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Publications

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

Tüshaus Johanna J   Müller Stephan A SA   Shrouder Joshua J   Arends Martina M   Simons Mikael M   Plesnila Nikolaus N   Blobel Carl P CP   Lichtenthaler Stefan F SF  

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20211101 11


Proteolytic ectodomain shedding of membrane proteins is a fundamental mechanism to control the communication between cells and their environment. A key protease for membrane protein shedding is ADAM17, which requires a non-proteolytic subunit, either inactive Rhomboid 1 (iRhom1) or iRhom2 for its activity. While iRhom1 and iRhom2 are co-expressed in most tissues and appear to have largely redundant functions, the brain is an organ with predominant expression of iRhom1. Yet, little is known about  ...[more]

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