Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidity.

Mario Ruiz,Rakesh Bodhicharla,Jan Boren,Kiran Busayavalasa,Hanna Ruhanen,Emma Svensk,Marcus Ståhlman,Henrik Palmgren,Marc Pilon

doi:10.7554/elife.47733

Abstract

The human AdipoR1 and AdipoR2 proteins, as well as their C. elegans homolog PAQR-2, protect against cell membrane rigidification by exogenous saturated fatty acids by regulating phospholipid composition. Here, we show that mutations in the C. elegans gene acs-13 help to suppress the phenotypes of paqr-2 mutant worms, including their characteristic membrane fluidity defects. acs-13 encodes a homolog of the human acyl-CoA synthetase ACSL1, and localizes to the mitochondrial membrane where it likely activates long chains fatty acids for import and degradation. Using siRNA combined with lipidomics and membrane fluidity assays (FRAP and Laurdan dye staining) we further show that the human ACSL1 potentiates lipotoxicity by the saturated fatty acid palmitate: silencing ACSL1 protects against the membrane rigidifying effects of palmitate and acts as a suppressor of AdipoR2 knockdown, thus echoing the C. elegans findings. We conclude that acs-13 mutations in C. elegans and ACSL1 knockdown in human cells prevent lipotoxicity by promoting increased levels of polyunsaturated fatty acid-containing phospholipids.

Highlights

Caenorhabditis elegans PAQR-2 and IGLR-2 form a complex at the plasma membrane that regulates fatty acid desaturation to protect against saturated fatty acid-induced membrane rigidification
Maintenance of membrane homeostasis is fundamental for most cellular processes and, given its importance, robust regulatory mechanisms must exist that adjust lipid composition to compensate for dietary variation
To better understand this phenomenon, we performed forward genetic screens in C. elegans and isolated mutants that improve tolerance to dietary saturated fatty acids. These include eight new loss of function alleles of the novel gene fld-1, one loss of function allele of acs-13 and one gain of function allele of paqr-1. fld-1 encodes a homolog of the human TLCD1/2 transmembrane proteins

Summary

Introduction

Caenorhabditis elegans PAQR-2 (a homolog of the mammalian AdipoR1 and AdipoR2 proteins) and IGLR-2 (homolog of the mammalian LRIG proteins) form a complex at the plasma membrane that regulates fatty acid desaturation to protect against saturated fatty acid-induced membrane rigidification. Institutionen för kemi och molekylärbiologi Naturvetenskapliga fakulteten 9.00 i Gösta Sandels, Institutionen för kemi och molekylärbiologi, Medicinaregatan 9B, Göteborg ISBN 978-91-7833-920-4 (PDF)

Results

Conclusion