The endoplasmic reticulum (ER) has an elaborate and dynamic architecture. This architecture is determined by multiple converging factors and forces including: membrane shaping proteins, dynamics on the cytoskeleton, and abundant contact sites that occur between the ER and other organelles. The result of this interplay is that the ER membrane is spread throughout the cytoplasm as a continuous membrane network made up of multiple functional and structural domains. How different domains can be generated and maintained within a continuous membrane bilayer is the focus of our work. To complement these questions, we also aim to understand the functions of different ER domains and the purpose of ER tubule dynamics. I previously demonstrated that a class of abundant and highly conserved integral membrane shaping proteins, the reticulons, function to stabilize the structure of of peripheral ER tubules in eukaryotes9. However, little is known about how reticulon membrane shaping activities are regulated during ER dynamics. We hypothesize that reticulon oligomerization and/or reversible phosphorylation are two testable and reasonable possible mechanisms for regulating reticulon function. We are also studying how new ER tubules are generated by dynamics on microtubules. Towards this goal, we recently identified a new factor Rab10 that localizes to a dynamic domain at the leading edge of dynamic ER tubules8. Our next goal is to understand how Rab10 dynamic domains are formed and regulated. Finally, we have recently shown that the ER tubules circumscribe mitochondria at the site of mitochondrial division17.
We aim to study the mechanisms and factors that drive ER contact and mitochondrial constriction and subsequent division at these positions.

Public Health Relevance

Very little is known about how the structures of membrane-bound organelles are generated. We are studying how the elaborate shape of the ER is generated and maintained. We have identified factors that regulate ER shape (reticulons) and ER dynamics (Rab10). We aim to identify how these factors are regulated. We have also identified new potential roles of ER tubules at contact sites with other organelles. Specifically, we showed that ER tubules mark the site of mitochondrial division. These data suggest that ER tubules are regulating the biogenesis of another organelle. We will continue to study how ER tubules regulate mitochondrial biogenesis at contact sites and what other factors might be involved.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM083977-06
Application #
8628573
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Ainsztein, Alexandra M
Project Start
2008-12-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
6
Fiscal Year
2014
Total Cost
$297,412
Indirect Cost
$96,737
Name
University of Colorado at Boulder
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Rowland, Ashley A; Chitwood, Patrick J; Phillips, Melissa J et al. (2014) ER contact sites define the position and timing of endosome fission. Cell 159:1027-41
English, Amber R; Voeltz, Gia K (2013) Endoplasmic reticulum structure and interconnections with other organelles. Cold Spring Harb Perspect Biol 5:a013227
English, Amber R; Voeltz, Gia K (2013) Rab10 GTPase regulates ER dynamics and morphology. Nat Cell Biol 15:169-78
Friedman, Jonathan R; Dibenedetto, Jared R; West, Matthew et al. (2013) Endoplasmic reticulum-endosome contact increases as endosomes traffic and mature. Mol Biol Cell 24:1030-40
Friedman, Jonathan R; Voeltz, Gia K (2011) The ER in 3D: a multifunctional dynamic membrane network. Trends Cell Biol 21:709-17
Zurek, Nesia; Sparks, Lenore; Voeltz, Gia (2011) Reticulon short hairpin transmembrane domains are used to shape ER tubules. Traffic 12:28-41
West, Matt; Zurek, Nesia; Hoenger, Andreas et al. (2011) A 3D analysis of yeast ER structure reveals how ER domains are organized by membrane curvature. J Cell Biol 193:333-46
Friedman, Jonathan R; Lackner, Laura L; West, Matthew et al. (2011) ER tubules mark sites of mitochondrial division. Science 334:358-62
Friedman, Jonathan R; Webster, Brant M; Mastronarde, David N et al. (2010) ER sliding dynamics and ER-mitochondrial contacts occur on acetylated microtubules. J Cell Biol 190:363-75
English, Amber R; Zurek, Nesia; Voeltz, Gia K (2009) Peripheral ER structure and function. Curr Opin Cell Biol 21:596-602