The γ-secretase substrate proteome and its role in cell signaling regulation

Pengfei Hou; Magdalena Zielonka; Lutgarde Serneels; Anna Martinez-Muriana; Nicola Fattorelli; Leen Wolfs; Suresh Poovathingal; Dries T'Syen; Sriram Balusu; Tom Theys; Mark Fiers; Renzo Mancuso; Andrew J. M. Howden; Bart De Strooper

doi:10.1016/j.molcel.2023.10.029

The γ-secretase substrate proteome and its role in cell signaling regulation

Pengfei Hou
, Magdalena Zielonka
, Lutgarde Serneels
, Anna Martinez-Muriana
, Nicola Fattorelli
, Leen Wolfs
, Suresh Poovathingal
, Dries T'Syen
, Sriram Balusu
, Tom Theys
, Mark Fiers
, Renzo Mancuso
, Andrew J. M. Howden
, Bart De Strooper (Lead / Corresponding author)

Cell Signalling and Immunology

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

212 Downloads (Pure)

Abstract

γ-Secretases mediate the regulated intramembrane proteolysis (RIP) of more than 150 integral membrane proteins. We developed an unbiased γ-secretase substrate identification (G-SECSI) method to study to what extent these proteins are processed in parallel. We demonstrate here parallel processing of at least 85 membrane proteins in human microglia in steady-state cell culture conditions. Pharmacological inhibition of γ-secretase caused substantial changes of human microglial transcriptomes, including the expression of genes related to the disease-associated microglia (DAM) response described in Alzheimer disease (AD). While the overall effects of γ-secretase deficiency on transcriptomic cell states remained limited in control conditions, exposure of mouse microglia to AD-inducing amyloid plaques strongly blocked their capacity to mount this putatively protective DAM cell state. We conclude that γ-secretase serves as a critical signaling hub integrating the effects of multiple extracellular stimuli into the overall transcriptome of the cell.

Original language	English
Pages (from-to)	4106-4122.e10
Number of pages	28
Journal	Molecular Cell
Volume	83
Issue number	22
DOIs	https://doi.org/10.1016/j.molcel.2023.10.029
Publication status	Published - 16 Nov 2023

Keywords

Mice
Animals
Humans
Amyloid Precursor Protein Secretases/genetics
Proteome/genetics
Signal Transduction
Membrane Proteins/metabolism
Alzheimer Disease/genetics
presenilin
intramembrane proteolysis
γ-secretase
Alzheimer's disease
microglia
substrate identification
tonic signaling

ASJC Scopus subject areas

Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.molcel.2023.10.029Licence: CC BY

Final published versionFinal published version, 10.1 MBLicence: CC BY

Cite this

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title = "The γ-secretase substrate proteome and its role in cell signaling regulation",

abstract = "γ-Secretases mediate the regulated intramembrane proteolysis (RIP) of more than 150 integral membrane proteins. We developed an unbiased γ-secretase substrate identification (G-SECSI) method to study to what extent these proteins are processed in parallel. We demonstrate here parallel processing of at least 85 membrane proteins in human microglia in steady-state cell culture conditions. Pharmacological inhibition of γ-secretase caused substantial changes of human microglial transcriptomes, including the expression of genes related to the disease-associated microglia (DAM) response described in Alzheimer disease (AD). While the overall effects of γ-secretase deficiency on transcriptomic cell states remained limited in control conditions, exposure of mouse microglia to AD-inducing amyloid plaques strongly blocked their capacity to mount this putatively protective DAM cell state. We conclude that γ-secretase serves as a critical signaling hub integrating the effects of multiple extracellular stimuli into the overall transcriptome of the cell.",

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author = "Pengfei Hou and Magdalena Zielonka and Lutgarde Serneels and Anna Martinez-Muriana and Nicola Fattorelli and Leen Wolfs and Suresh Poovathingal and Dries T'Syen and Sriram Balusu and Tom Theys and Mark Fiers and Renzo Mancuso and Howden, \{Andrew J. M.\} and \{De Strooper\}, Bart",

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doi = "10.1016/j.molcel.2023.10.029",

language = "English",

volume = "83",

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journal = "Molecular Cell",

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AU - Hou, Pengfei

AU - Zielonka, Magdalena

AU - Serneels, Lutgarde

AU - Martinez-Muriana, Anna

AU - Fattorelli, Nicola

AU - Wolfs, Leen

AU - Poovathingal, Suresh

AU - T'Syen, Dries

AU - Balusu, Sriram

AU - Theys, Tom

AU - Fiers, Mark

AU - Mancuso, Renzo

AU - Howden, Andrew J. M.

AU - De Strooper, Bart

PY - 2023/11/16

Y1 - 2023/11/16

N2 - γ-Secretases mediate the regulated intramembrane proteolysis (RIP) of more than 150 integral membrane proteins. We developed an unbiased γ-secretase substrate identification (G-SECSI) method to study to what extent these proteins are processed in parallel. We demonstrate here parallel processing of at least 85 membrane proteins in human microglia in steady-state cell culture conditions. Pharmacological inhibition of γ-secretase caused substantial changes of human microglial transcriptomes, including the expression of genes related to the disease-associated microglia (DAM) response described in Alzheimer disease (AD). While the overall effects of γ-secretase deficiency on transcriptomic cell states remained limited in control conditions, exposure of mouse microglia to AD-inducing amyloid plaques strongly blocked their capacity to mount this putatively protective DAM cell state. We conclude that γ-secretase serves as a critical signaling hub integrating the effects of multiple extracellular stimuli into the overall transcriptome of the cell.

AB - γ-Secretases mediate the regulated intramembrane proteolysis (RIP) of more than 150 integral membrane proteins. We developed an unbiased γ-secretase substrate identification (G-SECSI) method to study to what extent these proteins are processed in parallel. We demonstrate here parallel processing of at least 85 membrane proteins in human microglia in steady-state cell culture conditions. Pharmacological inhibition of γ-secretase caused substantial changes of human microglial transcriptomes, including the expression of genes related to the disease-associated microglia (DAM) response described in Alzheimer disease (AD). While the overall effects of γ-secretase deficiency on transcriptomic cell states remained limited in control conditions, exposure of mouse microglia to AD-inducing amyloid plaques strongly blocked their capacity to mount this putatively protective DAM cell state. We conclude that γ-secretase serves as a critical signaling hub integrating the effects of multiple extracellular stimuli into the overall transcriptome of the cell.

KW - Mice

KW - Animals

KW - Humans

KW - Amyloid Precursor Protein Secretases/genetics

KW - Proteome/genetics

KW - Signal Transduction

KW - Membrane Proteins/metabolism

KW - Alzheimer Disease/genetics

KW - presenilin

KW - intramembrane proteolysis

KW - γ-secretase

KW - Alzheimer's disease

KW - microglia

KW - substrate identification

KW - tonic signaling

U2 - 10.1016/j.molcel.2023.10.029

DO - 10.1016/j.molcel.2023.10.029

M3 - Article

C2 - 37977120

SN - 1097-2765

VL - 83

SP - 4106-4122.e10

JO - Molecular Cell

JF - Molecular Cell

IS - 22

ER -

The γ-secretase substrate proteome and its role in cell signaling regulation

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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