TY - JOUR T1 - Genome-wide synthetic lethal CRISPR screen identifies <em>FIS1</em> as a genetic interactor of ALS-linked <em>C9ORF72</em> JF - bioRxiv DO - 10.1101/778118 SP - 778118 AU - Noori Chai AU - Michael S. Haney AU - Julien Couthouis AU - David W. Morgens AU - Alyssa Benjamin AU - Kathryn Wu AU - James Ousey AU - Shirleen Fang AU - Sarah Finer AU - Michael C. Bassik AU - Aaron D. Gitler Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/09/21/778118.abstract N2 - 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. ER -