The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis.

Genes Dev
Authors
Keywords
Abstract

While a mutation in is the most common genetic contributor to amyotrophic lateral sclerosis (ALS), much remains to be learned concerning the function of the protein normally encoded at this locus. To elaborate further on functions for C9ORF72, we used quantitative mass spectrometry-based proteomics to identify interacting proteins in motor neurons and found that its long isoform complexes with and stabilizes SMCR8, which further enables interaction with WDR41. To study the organismal and cellular functions for this tripartite complex, we generated loss-of-function mutant mice and found that they developed phenotypes also observed in loss-of-function animals, including autoimmunity. Along with a loss of tolerance for many nervous system autoantigens, we found increased lysosomal exocytosis in mutant macrophages. In addition to elevated surface Lamp1 (lysosome-associated membrane protein 1) expression, we also observed enhanced secretion of lysosomal components-phenotypes that we subsequently observed in loss-of-function macrophages. Overall, our findings demonstrate that C9ORF72 and SMCR8 have interdependent functions in suppressing autoimmunity as well as negatively regulating lysosomal exocytosis-processes of potential importance to ALS.

Year of Publication
2018
Journal
Genes Dev
Volume
32
Issue
13-14
Pages
929-943
Date Published
2018 07 01
ISSN
1549-5477
DOI
10.1101/gad.313932.118
PubMed ID
29950492
PubMed Central ID
PMC6075033
Links
Grant list
R01 NS089742 / NS / NINDS NIH HHS / United States