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LSSS 2017-2018


Life Sciences Seminar Series


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Gia Voeltz

Colorado State University, Boulder CO, USA

Factors and functions of ER contact sites with other organelles

Selected Publications

SnapShot: Functions of Endoplasmic Reticulum Membrane Contact Sites.Salvador-Gallego R, Hoyer MJ, Voeltz GK
Cell 2017 Nov 16; 171(5):1224-1224.e1


The endoplasmic reticulum (ER) consists of the nuclear envelope and a reticulated interconnected network of tubules and sheets. ER sheets are studded with ribosomes and provide the entryway for proteins into the secretory pathway. ER tubules move dynamically on microtubules and form membrane contact sites with other organelles, where membranes are tethered, but not fused. This Snapshot reviews key biological processes that take place at ER contact sites with the Golgi, endosomes, and mitochondria.

Multiple dynamin family members collaborate to drive mitochondrial division.Lee JE, Westrate LM, Wu H, Page C, Voeltz GK
Nature 2016 Dec 1; 540(7631):139-143


Mitochondria cannot be generated de novo; they must grow, replicate their genome, and divide in order to be inherited by each daughter cell during mitosis. Mitochondrial division is a structural challenge that requires the substantial remodelling of membrane morphology. Although division factors differ across organisms, the need for multiple constriction steps and a dynamin-related protein (Drp1, Dnm1 in yeast) has been conserved. In mammalian cells, mitochondrial division has been shown to proceed with at least two sequential constriction steps: the endoplasmic reticulum and actin must first collaborate to generate constrictions suitable for Drp1 assembly on the mitochondrial outer membrane; Drp1 then further constricts membranes until mitochondrial fission occurs. In vitro experiments, however, indicate that Drp1 does not have the dynamic range to complete membrane fission. In contrast to Drp1, the neuron-specific classical dynamin dynamin-1 (Dyn1) has been shown to assemble on narrower lipid profiles and facilitate spontaneous membrane fission upon GTP hydrolysis. Here we report that the ubiquitously expressed classical dynamin-2 (Dyn2) is a fundamental component of the mitochondrial division machinery. A combination of live-cell and electron microscopy in three different mammalian cell lines reveals that Dyn2 works in concert with Drp1 to orchestrate sequential constriction events that build up to division. Our work underscores the biophysical limitations of Drp1 and positions Dyn2, which has intrinsic membrane fission properties, at the final step of mitochondrial division.

Structure and function of ER membrane contact sites with other organelles.Phillips MJ, Voeltz GK
Nat Rev Mol Cell Biol 2016 Feb; 17(2):69-82


The endoplasmic reticulum (ER) is the largest organelle in the cell, and its functions have been studied for decades. The past several years have provided novel insights into the existence of distinct domains between the ER and other organelles, known as membrane contact sites (MCSs). At these contact sites, organelle membranes are closely apposed and tethered, but do not fuse. Here, various protein complexes can work in concert to perform specialized functions such as binding, sensing and transferring molecules, as well as engaging in organelle biogenesis and dynamics. This Review describes the structure and functions of MCSs, primarily focusing on contacts of the ER with mitochondria and endosomes.

ER contact sites define the position and timing of endosome fission.Rowland AA, Chitwood PJ, Phillips MJ, Voeltz GK
Cell 2014 Nov 20; 159(5):1027-1041


Endocytic cargo and Rab GTPases are segregated to distinct domains of an endosome. These domains maintain their identity until they undergo fission to traffic cargo. It is not fully understood how segregation of cargo or Rab proteins is maintained along the continuous endosomal membrane or what machinery is required for fission. Endosomes form contact sites with the endoplasmic reticulum (ER) that are maintained during trafficking. Here, we show that stable contacts form between the ER and endosome at constricted sorting domains, and free diffusion of cargo is limited at these positions. We demonstrate that the site of constriction and fission for early and late endosomes is spatially and temporally linked to contact sites with the ER. Lastly, we show that altering ER structure and dynamics reduces the efficiency of endosome fission. Together, these data reveal a surprising role for ER contact in defining the timing and position of endosome fission.

Cell organelles.Voeltz GK, Barr FA
Curr Opin Cell Biol 2013 Aug; 25(4):403-5


Endoplasmic reticulum structure and interconnections with other organelles.English AR, Voeltz GK
Cold Spring Harb Perspect Biol 2013 Apr 1; 5(4):a013227


The endoplasmic reticulum (ER) is a large, continuous membrane-bound organelle comprised of functionally and structurally distinct domains including the nuclear envelope, peripheral tubular ER, peripheral cisternae, and numerous membrane contact sites at the plasma membrane, mitochondria, Golgi, endosomes, and peroxisomes. These domains are required for multiple cellular processes, including synthesis of proteins and lipids, calcium level regulation, and exchange of macromolecules with various organelles at ER-membrane contact sites. The ER maintains its unique overall structure regardless of dynamics or transfer at ER-organelle contacts. In this review, we describe the numerous factors that contribute to the structure of the ER.

Rab10 GTPase regulates ER dynamics and morphology.English AR, Voeltz GK
Nat Cell Biol 2013 Feb; 15(2):169-78


We have identified Rab10 as an ER-specific Rab GTPase that regulates ER structure and dynamics. We show that Rab10 localizes to the ER and to dynamic ER-associated structures that track along microtubules and mark the position of new ER tubule growth. Rab10 depletion or expression of a Rab10 GDP-locked mutant alters ER morphology, resulting in fewer ER tubules. We demonstrate that this defect is due to a reduced ability of dynamic ER tubules to grow out and successfully fuse with adjacent ER. Consistent with this function, Rab10 partitions to dynamic ER-associated domains found at the leading edge of almost half of all dynamic ER tubules. Interestingly, this Rab10 domain is highly enriched with at least two ER enzymes that regulate phospholipid synthesis, phosphatidylinositol synthase (PIS) and CEPT1. Both the formation and function of this Rab10/PIS/CEPT1 dynamic domain are inhibited by expression of a GDP-locked Rab10 mutant. Together, these data demonstrate that Rab10 regulates ER dynamics and further suggest that these dynamics could be coupled to phospholipid synthesis.