Translational control of human acetyl-CoA carboxylase 1 mRNA is mediated by an internal ribosome entry site in response to ER stress, serum deprivation or hypoxia mimetic CoCl2

Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Apr;1863(4):388-398. doi: 10.1016/j.bbalip.2018.01.006. Epub 2018 Jan 16.

Abstract

Acetyl-CoA carboxylase 1 (ACC1) is a cytosolic enzyme catalyzing the rate limiting step in de novo fatty acid biosynthesis. There is mounting evidence showing that ACC1 is susceptible to dysregulation and that it is over-expressed in liver diseases associated with lipid accumulation and in several cancers. In the present study, ACC1 regulation at the translational level is reported. Using several experimental approaches, the presence of an internal ribosome entry site (IRES) has been established in the 5' untranslated region (5' UTR) of the ACC1 mRNA. Transfection experiments with the ACC1 5' UTR inserted in a dicistronic reporter vector show a remarkable increase in the downstream cistron translation, through a cap-independent mechanism. The endoplasmic reticulum (ER) stress condition and the related unfolded protein response (UPR), triggered by treatment with thapsigargin and tunicamycin, cause an increase of the cap-independent translation of ACC1 mRNA in HepG2 cells, despite the overall reduction in global protein synthesis. Other stress conditions, such as serum starvation and incubation with hypoxia mimetic agent CoCl2, up-regulate ACC1 expression in HepG2 cells at the translational level. Overall, these findings indicate that the presence of an IRES in the ACC1 5' UTR allows ACC1 mRNA translation in conditions that are inhibitory to cap-dependent translation. A potential involvement of the cap-independent translation of ACC1 in several pathologies, such as obesity and cancer, has been discussed.

Keywords: Acetyl-CoA carboxylase; Endoplasmic reticulum stress; Internal ribosome entry site; Lipid metabolism dysregulation; Lipogenesis; Translational reprogramming.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / genetics
  • Acetyl-CoA Carboxylase / genetics*
  • Acetyl-CoA Carboxylase / metabolism
  • Cell Hypoxia / drug effects
  • Cell Survival / drug effects
  • Cobalt / pharmacology*
  • Culture Media, Serum-Free
  • Endoplasmic Reticulum Stress / drug effects*
  • Hep G2 Cells
  • Humans
  • Internal Ribosome Entry Sites / genetics*
  • Plasmids / metabolism
  • Protein Biosynthesis* / drug effects
  • RNA Splicing / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism

Substances

  • 5' Untranslated Regions
  • Culture Media, Serum-Free
  • Internal Ribosome Entry Sites
  • RNA, Messenger
  • Cobalt
  • Acetyl-CoA Carboxylase
  • cobaltous chloride