The formation and function of ER-endosome membrane contact sites

Emily R Eden

doi:10.1016/j.bbalip.2016.01.020

Abstract

Recent advances in membrane contact site (MCS) biology have revealed key roles for MCSs in inter-organellar exchange, the importance of which is becoming increasingly apparent. Roles for MCSs in many essential physiological processes including lipid transfer, calcium exchange, receptor tyrosine kinase signalling, lipid droplet formation, autophagosome formation, organelle dynamics and neurite outgrowth have been reported. The ER forms an extensive and dynamic network of MCSs with a diverse range of functionally distinct organelles. MCSs between the ER and endocytic pathway are particularly abundant, suggesting important physiological roles. Here, our current knowledge of the formation and function of ER contact sites with endocytic organelles from studies in mammalian systems is reviewed. Their relatively poorly defined molecular composition and recently identified functions are discussed. In addition, likely, but yet to be established, roles for these contacts in lipid transfer and calcium signalling are considered. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon.

Highlights

Membrane contact sites (MCSs) are regions of close apposition (≤ 30 nm) between two organelles, establishing microdomains for interorganellar exchange
ER:mitochondrial MCSs are promoted by VAPB:PTPIP51 interaction [7],while ER:Golgi MCSs are promoted by VAP interaction with OSBP, CERT and Nir2 FFAT motifs [8]
Just as there are multiple populations of endocytic organelles [13,60], it seems likely that multiple populations of ER contact sites with endocytic organelles exist, with organelle-specific tethering complexes, that might for example, be recruited by Rab5 or Rab7, markers of early or late endosomes respectively

Summary

Introduction

Membrane contact sites (MCSs) are regions of close apposition (≤ 30 nm) between two organelles, establishing microdomains for interorganellar exchange. The first indication that the ER might make functional contact sites with endocytic organelles came from studies in yeast that identified a junction between the nucleus and vacuole formed by direct interaction between the ER protein Nvj and the vacuole protein Vac8 [1]. Membrane contact sites are stabilized by tethering complexes that maintain close proximity between the apposing membranes without membrane fusion. These tethers can often be discerned by electron microscopy, as multiple strands between the apposing membranes of the two organelles (Fig. 1). VAP interaction with the FFAT motifs of the sterol binding proteins ORP1L [3] and STARD3 [10] on late endosomes/lysosomes have been implicated in MCS formation between the ER and the endocytic pathway, as will be discussed in more detail below

ER-endosome contact site formation

Endosome fission and positioning

Regulation of growth factor receptors

Lipid transport

Calcium signalling

Conclusions and perspectives