Lipase maturation factor 1 affects redox homeostasis in the endoplasmic reticulum

EMBO J. 2018 Oct 1;37(19):e97379. doi: 10.15252/embj.201797379. Epub 2018 Aug 1.

Abstract

Lipoprotein lipase (LPL) is a secreted lipase that clears triglycerides from the blood. Proper LPL folding and exit from the endoplasmic reticulum (ER) require lipase maturation factor 1 (LMF1), an ER-resident transmembrane protein, but the mechanism involved is unknown. We used proteomics to identify LMF1-binding partners necessary for LPL secretion in HEK293 cells and found these to include oxidoreductases and lectin chaperones, suggesting that LMF1 facilitates the formation of LPL's five disulfide bonds. In accordance with this role, we found that LPL aggregates in LMF1-deficient cells due to the formation of incorrect intermolecular disulfide bonds. Cells lacking LMF1 were hypersensitive to depletion of glutathione, but not DTT treatment, suggesting that LMF1 helps reduce the ER Accordingly, we found that loss of LMF1 results in a more oxidized ER Our data show that LMF1 has a broader role than simply folding lipases, and we identified fibronectin and the low-density lipoprotein receptor (LDLR) as novel LMF1 clients that contain multiple, non-sequential disulfide bonds. We conclude that LMF1 is needed for secretion of some ER client proteins that require reduction of non-native disulfides during their folding.

Keywords: disulfide bonds; lipase maturation factor 1; lipoprotein lipase; protein folding; redox.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Disulfides / metabolism
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Fibronectins / genetics
  • Fibronectins / metabolism
  • Glutathione / genetics
  • Glutathione / metabolism
  • HEK293 Cells
  • Homeostasis*
  • Humans
  • Lipoprotein Lipase / genetics
  • Lipoprotein Lipase / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Oxidation-Reduction
  • Protein Folding*
  • Proteomics
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism

Substances

  • Disulfides
  • Fibronectins
  • LDLR protein, human
  • LMF1 protein, human
  • Membrane Proteins
  • Receptors, LDL
  • LPL protein, human
  • Lipoprotein Lipase
  • Glutathione