Perilipin membrane integration determines lipid droplet heterogeneity in differentiating adipocytes
Mario Majchrzak,
Ozren Stojanović,
Dalila Ajjaji,
Kalthoum Ben M’barek,
Mohyeddine Omrane,
Abdou Rachid Thiam,
Robin W. Klemm
Affiliations
Mario Majchrzak
Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland
Ozren Stojanović
Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3PT, UK
Dalila Ajjaji
Laboratoire de Physique de l’École Normale Supérieure (ENS), Université PSL, CNRS, Sorbonne Université, Université de Paris, 75005 Paris, France
Kalthoum Ben M’barek
Laboratoire de Physique de l’École Normale Supérieure (ENS), Université PSL, CNRS, Sorbonne Université, Université de Paris, 75005 Paris, France
Mohyeddine Omrane
Laboratoire de Physique de l’École Normale Supérieure (ENS), Université PSL, CNRS, Sorbonne Université, Université de Paris, 75005 Paris, France
Abdou Rachid Thiam
Laboratoire de Physique de l’École Normale Supérieure (ENS), Université PSL, CNRS, Sorbonne Université, Université de Paris, 75005 Paris, France
Robin W. Klemm
Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3PT, UK; Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland; Corresponding author
Summary: The storage of fat within lipid droplets (LDs) of adipocytes is critical for whole-body health. Acute fatty acid (FA) uptake by differentiating adipocytes leads to the formation of at least two LD classes marked by distinct perilipins (PLINs). How this LD heterogeneity arises is an important yet unresolved cell biological problem. Here, we show that an unconventional integral membrane segment (iMS) targets the adipocyte specific LD surface factor PLIN1 to the endoplasmic reticulum (ER) and facilitates high-affinity binding to the first LD class. The other PLINs remain largely excluded from these LDs until FA influx recruits them to a second LD population. Preventing ER targeting turns PLIN1 into a soluble, cytoplasmic LD protein, reduces its LD affinity, and switches its LD class specificity. Conversely, moving the iMS to PLIN2 leads to ER insertion and formation of a separate LD class. Our results shed light on how differences in organelle targeting and disparities in lipid affinity of LD surface factors contribute to formation of LD heterogeneity.
