FIT2 organizes lipid droplet biogenesis with ER tubule-forming proteins and septins

J Cell Biol. 2021 May 3;220(5):e201907183. doi: 10.1083/jcb.201907183.


Lipid droplets (LDs) are critical for lipid storage and energy metabolism. LDs form in the endoplasmic reticulum (ER). However, the molecular basis for LD biogenesis remains elusive. Here, we show that fat storage-inducing transmembrane protein 2 (FIT2) interacts with ER tubule-forming proteins Rtn4 and REEP5. The association is mainly transmembrane domain based and stimulated by oleic acid. Depletion of ER tubule-forming proteins decreases the number and size of LDs in cells and Caenorhabditis elegans, mimicking loss of FIT2. Through cytosolic loops, FIT2 binds to cytoskeletal protein septin 7, an interaction that is also required for normal LD biogenesis. Depletion of ER tubule-forming proteins or septins delays nascent LD formation. In addition, FIT2-interacting proteins are up-regulated during adipocyte differentiation, and ER tubule-forming proteins, septin 7, and FIT2 are transiently enriched at LD formation sites. Thus, FIT2-mediated nascent LD biogenesis is facilitated by ER tubule-forming proteins and septins.

Publication types

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

MeSH terms

  • Animals
  • COS Cells
  • Caenorhabditis elegans / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Endoplasmic Reticulum / metabolism*
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Lipid Droplets / metabolism*
  • Lipid Metabolism / physiology
  • Membrane Proteins / metabolism*
  • Nogo Proteins / metabolism
  • Septins / metabolism*


  • FITM2 protein, human
  • Membrane Proteins
  • Nogo Proteins
  • Septins