A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy.
The intronic GGGGCC hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) is a prevalent genetic abnormality identified in both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8) is a protein with unclear functions. We report that C9ORF72 is a component of a multiprotein complex containing SMCR8, WDR41, and ATG101 (an important regulator of autophagy). The C9ORF72 complex displays guanosine triphosphatase (GTPase) activity and acts as a guanosine diphosphate-guanosine 5'-triphosphate (GDP-GTP) exchange factor (GEF) for RAB39B. We created Smcr8 knockout mice and found that Smcr8 mutant cells exhibit impaired autophagy induction, which is similarly observed in C9orf72 knockdown cells. Mechanistically, SMCR8/C9ORF72 interacts with the key autophagy initiation ULK1 complex and regulates expression and activity of ULK1. The complex has an additional role in regulating later stages of autophagy. Whereas autophagic flux is enhanced in C9orf72 knockdown cells, depletion of Smcr8 results in a reduced flux with an abnormal expression of lysosomal enzymes. Thus, C9ORF72 and SMCR8 have similar functions in modulating autophagy induction by regulating ULK1 and play distinct roles in regulating autophagic flux.
Department of Genetics and Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
Mei
0000-0002-7207-3159
M
Yang
Department of Genetics and Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
Chen
C
Liang
Department of Biological Sciences, National University of Singapore, 117543 Singapore.
Kunchithapadam
0000-0001-7940-1090
K
Swaminathan
Department of Genetics and Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
Stephanie
0000-0002-6049-0246
S
Herrlinger
Department of Human Genetics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Fan
0000-0002-0568-2616
F
Lai
Department of Human Genetics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Ramin
R
Shiekhattar
Department of Genetics and Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
Jian-Fu
JF
Chen
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071189:Autophagy-Related Protein-1 Homolog / Q000235:genetics*; D000073885:C9orf72 Protein / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D042622:DNA Repeat Expansion / Q000235:genetics; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D002352:Carrier Proteins; C000618232:SMCR8 protein, mouse; D000071189:Autophagy-Related Protein-1 Homolog; C112444:Ulk1 protein, mouse
C9ORF72; SMCR8; ULK1; autophagic flux; autophagy induction