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The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis
- Source :
- Genes & Development. 32:929-943
- Publication Year :
- 2018
- Publisher :
- Cold Spring Harbor Laboratory, 2018.
-
Abstract
- While a mutation in C9ORF72 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 Smcr8 loss-of-function mutant mice and found that they developed phenotypes also observed in C9orf72 loss-of-function animals, including autoimmunity. Along with a loss of tolerance for many nervous system autoantigens, we found increased lysosomal exocytosis in Smcr8 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 C9orf72 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.
- Subjects :
- 0301 basic medicine
Gene isoform
Mutant
Autoimmunity
Biology
Proteomics
Exocytosis
Mice
03 medical and health sciences
Lysosomal-Associated Membrane Protein 1
C9orf72
Lysosome
Genetics
medicine
Animals
Humans
Protein Isoforms
Secretion
Mice, Knockout
C9orf72 Protein
LAMP1
Protein Stability
Macrophages
Amyotrophic Lateral Sclerosis
Cell biology
030104 developmental biology
medicine.anatomical_structure
Gene Expression Regulation
Membrane protein
Mutation
Splenomegaly
Lymph Nodes
Carrier Proteins
Lysosomes
Research Paper
Developmental Biology
Subjects
Details
- ISSN :
- 15495477 and 08909369
- Volume :
- 32
- Database :
- OpenAIRE
- Journal :
- Genes & Development
- Accession number :
- edsair.doi.dedup.....2d60cec24cbd25ce2b767672a0e42e5f