Identification of a novel anoikis signalling pathway using the fungal virulence factor gliotoxin

Nature Communications
F HaunC Borner

Abstract

Anoikis is a form of apoptosis induced by cell detachment. Integrin inactivation plays a major role in the process but the exact signalling pathway is ill-defined. Here we identify an anoikis pathway using gliotoxin (GT), a virulence factor of the fungus Aspergillus fumigatus, which causes invasive aspergillosis in humans. GT prevents integrin binding to RGD-containing extracellular matrix components by covalently modifying cysteines in the binding pocket. As a consequence, focal adhesion kinase (FAK) is inhibited resulting in dephosphorylation of p190RhoGAP, allowing activation of RhoA. Sequential activation of ROCK, MKK4/MKK7 and JNK then triggers pro-apoptotic phosphorylation of Bim. Cells in suspension or lacking integrin surface expression are insensitive to GT but are sensitised to ROCK-MKK4/MKK7-JNK-dependent anoikis upon attachment to fibronectin or integrin upregulation. The same signalling pathway is triggered by FAK inhibition or inhibiting integrin αV/β3 with Cilengitide. Thus, GT can target integrins to induce anoikis on lung epithelial cells.

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Citations

Sep 11, 2019·Cells·Hung-Chi YangDaniel Tsun-Yee Chiu
Dec 21, 2019·Nature Microbiology·Natasha Lopes FischerIgor E Brodsky
Feb 15, 2020·New Zealand Veterinary Journal·T W Jordan
May 8, 2020·Aging·Hyun-Ji ChoYoung-Sam Lee
Feb 18, 2020·Frontiers in Plant Science·Yanjing GuoSheng Qiang
Nov 4, 2020·Planta medica·Diego V WilkeLeticia V Costa-Lotufo
Mar 18, 2021·BioMed Research International·Murong ZhouQian Zhang
Apr 28, 2021·Brain Tumor Pathology·Chaoying QinQing Liu

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Datasets Mentioned

BETA
ERR1406032

Methods Mentioned

BETA
GTPases
pulldowns
GTPase
pulldown
fluorescence-activated cell sorting
FACS
PMA
RNAseq
PCR
electrophoresis

Software Mentioned

Agilent QuikChange Primer Design Tool
FusionCapt Advance Solo
Metamorph
R library
PeptideProphet
DBtoolkit
Ensembl
kallisto
tximport
Bioconductor package

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