A C9orf72–CARM1 axis regulates lipid metabolism under glucose starvation-induced nutrient stress
- Yang Liu1,2,
- Tao Wang1,2,
- Yon Ju Ji1,2,
- Kenji Johnson1,2,
- Honghe Liu1,2,
- Kaitlin Johnson1,
- Scott Bailey1,
- Yongwon Suk1,2,
- Yu-Ning Lu1,2,
- Mingming Liu1,2 and
- Jiou Wang1,2
- 1Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA;
- 2Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA
- Corresponding author: jiouw{at}jhu.edu
Abstract
Cells undergo metabolic adaptation during environmental changes by using evolutionarily conserved stress response programs. This metabolic homeostasis is exquisitely regulated, and its imbalance could underlie human pathological conditions. We report here that C9orf72, which is linked to the most common forms of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is a key regulator of lipid metabolism under stress. Loss of C9orf72 leads to an overactivation of starvation-induced lipid metabolism that is mediated by dysregulated autophagic digestion of lipids and increased de novo fatty acid synthesis. C9orf72 acts by promoting the lysosomal degradation of coactivator-associated arginine methyltransferase 1 (CARM1), which in turn regulates autophagy–lysosomal functions and lipid metabolism. In ALS/FTD patient-derived neurons or tissues, a reduction in C9orf72 function is associated with dysregulation in the levels of CARM1, fatty acids, and NADPH oxidase NOX2. These results reveal a C9orf72–CARM1 axis in the control of stress-induced lipid metabolism and implicates epigenetic dysregulation in relevant human diseases.
Keywords
Footnotes
-
Supplemental material is available for this article.
-
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.315564.118.
- Received April 11, 2018.
- Accepted August 27, 2018.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.