Genome-wide synthetic lethal CRISPR screen identifies FIS1 as a genetic interactor of ALS-linked C9ORF72.
Amyotrophic Lateral Sclerosis
/ genetics
C9orf72 Protein
/ genetics
Clustered Regularly Interspaced Short Palindromic Repeats
Gene Knockout Techniques
/ methods
Genetic Testing
Humans
Membrane Proteins
/ genetics
Mitochondrial Proteins
/ genetics
RNA-Seq
Synthetic Lethal Mutations
/ genetics
U937 Cells
C9ORF72
CRISPR
FIS1
Synthetic lethal screen
Journal
Brain research
ISSN: 1872-6240
Titre abrégé: Brain Res
Pays: Netherlands
ID NLM: 0045503
Informations de publication
Date de publication:
01 02 2020
01 02 2020
Historique:
received:
07
12
2019
revised:
10
12
2019
accepted:
12
12
2019
pubmed:
18
12
2019
medline:
24
4
2021
entrez:
18
12
2019
Statut:
ppublish
Résumé
Mutations in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis (ALS). Both toxic gain of function and loss of function pathogenic mechanisms have been proposed. Accruing evidence from mouse knockout studies point to a role for C9ORF72 as a regulator of immune function. To provide further insight into its cellular function, we performed a genome-wide synthetic lethal CRISPR screen in human myeloid cells lacking C9ORF72. We discovered a strong synthetic lethal genetic interaction between C9ORF72 and FIS1, which encodes a mitochondrial membrane protein involved in mitochondrial fission and mitophagy. Mass spectrometry experiments revealed that in C9ORF72 knockout cells, FIS1 strongly bound to a class of immune regulators that activate the receptor for advanced glycation end (RAGE) products and trigger inflammatory cascades. These findings present a novel genetic interactor for C9ORF72 and suggest a compensatory role for FIS1 in suppressing inflammatory signaling in the absence of C9ORF72.
Identifiants
pubmed: 31843624
pii: S0006-8993(19)30655-9
doi: 10.1016/j.brainres.2019.146601
pmc: PMC7539795
mid: NIHMS1547405
pii:
doi:
Substances chimiques
C9orf72 Protein
0
FIS1 protein, human
0
Membrane Proteins
0
Mitochondrial Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
146601Subventions
Organisme : NINDS NIH HHS
ID : R35 NS097263
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG000044
Pays : United States
Organisme : NIMH NIH HHS
ID : T32 MH020016
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.
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