Bringing light to ER contacts and a new phase in organelle communication

Abstract

Functioning cells depend on the outward-facing plasma membrane (PM) effectively contacting the endoplasmic reticulum (ER), which serves as a central hub for contacts with mitochondria and other intracellular organelles. The contact sites are critical to intracellular communication because they mediate intermembrane exchange of lipids, ions, and other small molecules that both maintain competent organelles and modulate their activities. The targeting of molecular interactions within and between these cellular membranes underlies a cell’s vitality in its homeostatic environment, and, using the same dynamic infrastructure, the cell is also poised to respond to environmental stimuli. A major question driving current research efforts is how interorganelle contact sites are organized and regulated such that the membranes connect and exchange molecules appropriately. Protein partners serving as tethers have been demonstrated for some intermembrane contact sites, and lipid-based phase separation has been suggested as another possible means for selective targeting of contact-site proteins. However, detailed characterization of contact sites has been hindered by the complexity of the membrane interfaces, which interact dynamically within an intricately networked system (1). In a step to surmount this limitation, King et al. (2) describe the use of hypotonic swelling to create large intracellular vesicles (LICVs) from the ER and other organelles. LICVs both separate the organelle membranes and magnify organelle contacts, providing a relatively simple approach for examining the underlying organization of proteins and lipids. As part of their initial characterization, the authors identify tether proteins in LICV-retained contacts that are known to participate in molecular exchanges across these membranes. Especially exciting is their evidence that ER membranes have the capacity for order/disorder phase separation, which was previously characterized in giant PM vesicles (GPMVs) (3) and may play a similar role sorting proteins in contact sites (Fig. 1). Fig. 1. ER-LICVs are created within cells by hypotonic swelling and retain … [↵][1]1To whom correspondence may be addressed. Email: bab13{at}cornell.edu. [1]: #xref-corresp-1-1