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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 pro...

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Autores principales: Yang, Mei, Liang, Chen, Swaminathan, Kunchithapadam, Herrlinger, Stephanie, Lai, Fan, Shiekhattar, Ramin, Chen, Jian-Fu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010369/
https://www.ncbi.nlm.nih.gov/pubmed/27617292
http://dx.doi.org/10.1126/sciadv.1601167
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author Yang, Mei
Liang, Chen
Swaminathan, Kunchithapadam
Herrlinger, Stephanie
Lai, Fan
Shiekhattar, Ramin
Chen, Jian-Fu
author_facet Yang, Mei
Liang, Chen
Swaminathan, Kunchithapadam
Herrlinger, Stephanie
Lai, Fan
Shiekhattar, Ramin
Chen, Jian-Fu
author_sort Yang, Mei
collection PubMed
description 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.
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spelling pubmed-50103692016-09-09 A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy Yang, Mei Liang, Chen Swaminathan, Kunchithapadam Herrlinger, Stephanie Lai, Fan Shiekhattar, Ramin Chen, Jian-Fu Sci Adv Research Articles 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. American Association for the Advancement of Science 2016-09-02 /pmc/articles/PMC5010369/ /pubmed/27617292 http://dx.doi.org/10.1126/sciadv.1601167 Text en Copyright © 2016, The Authors http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Yang, Mei
Liang, Chen
Swaminathan, Kunchithapadam
Herrlinger, Stephanie
Lai, Fan
Shiekhattar, Ramin
Chen, Jian-Fu
A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy
title A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy
title_full A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy
title_fullStr A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy
title_full_unstemmed A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy
title_short A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy
title_sort c9orf72/smcr8-containing complex regulates ulk1 and plays a dual role in autophagy
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010369/
https://www.ncbi.nlm.nih.gov/pubmed/27617292
http://dx.doi.org/10.1126/sciadv.1601167
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