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Jokitalo Group
Morphological and functional subdomains of the endoplasmic reticulum

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Endoplasmic reticulum (ER) comprises a highly dynamic, continuous and singular 3D network with diverse structural and functional domains. ER has a crucial role in the synthesis, modification and transport of secretory and membrane proteins, and is the site for the biosynthesis, processing and transport of several lipids. In addition, ER forms specialized regions such as sites for vesicular export (ERES) and areas that contact the other membrane-bound organelles in the cell, including the Golgi complex, mitochondria, endosomes, peroxisomes, lipid droplets, phagophores and the plasma membrane (Fig 1).
Figure 1
Fig. 1. ERES, ER-Mitochodria contacts, ER-Lipid droplet contacts, ER-Phagophore

Proper ER operation requires an intricate balance between ER dynamics, morphology, and functions. Defective ER functions, especially the onset of unfolded protein response as a consequence of damaged protein folding machinery, can lead to triggering of cell death which are implicated in several diseases. In addition, a direct connection between defective ER morphology and resulting clinical feature have been implicated in few cases (for references see for example Roussel et al., 2013; Orso et al., 2009; Park et al., 2010; Zuchner et al., 2004). Despite its indisputable central role in cell fate decisions, its dynamics, interactions with other cellular compartments and molecular interactions of ER-resident proteins within and outside ER membranes are still poorly characterized.
Structurally ER is composed of two forms, tubules and flattened sheets, which branch to generate a polygonal network (Fig. 2). Depending on cell types, ER can adopt a wide range of different organizations, and different cells exhibit varying sheet morphologies.
Figure 2
Fig 2. Basic building blocks of ER: the tubules and sheets.

In addition of being a structure in flux and constantly rearranging, the balance between ER sheets and tubules and the distribution of the network within the cell are both cell type (Fig. 3) and cell cycle dependent (Fig. 4).
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ER (yellow) network organization in CHO-K1 cells
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ER (yellow) network organization in Trypanosoma.
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Fig3. ER (yellow) network organization in Saccaromyces cerevisiae.
Fig3. ER (yellow) network organization in CHO-K1, Trypanosoma and Saccaromyces cerevisiae.

Recently, we showed that ER network organization during cell cycle is highly plastic as the mitotic ER has strikingly different morphology than interphase ER. The observed loss of membrane-bound ribosomes and the sheets-to-tubule transition might reflect the decrease in protein translation, an important function especially assigned for ER sheets. Moreover, we found that NE partitions as part of the reticular ER and the daughter cells inherit ER as a continuous network (Puhka et al., 2007; Puhka et al., 2012).
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The reorganization of ER into concentric layers seems to be more predominant toward the end of metaphase.
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Model of mitotic sheet-to-tubule transformation. The transformation of rough ER starts from intact or fenestrated sheets and proceeds toward a more fenestrated state that can eventually produce structures resembling tubular networks.
Fig4. Cell cycle dependent organization of ER. (click on the images to enlarge)

Our main research interests are:
  • How are the morphological subdomains of ER created?
  • What factors are involved in the ER tubule and sheet morphogenesis and what are the interaction partners?
  • And finally, how the defined subdomains are related to the ER functions and dynamics?

We are studying both membrane proteins involved in the creation of membrane curvature resulting in ER tubule formation, as well as cytoskeletal factors involved in ER sheet morphogenesis and dynamics.

One of the main projects concerns hairpin forming membrane proteins, the reticulons and their interaction partners, which have been suggested to be liable for curvature generation and ultimately creating and maintaining ER tubules (Voeltz et al., 2006). We are also interested in the cell cycle dependent changes in the protein expression levels of the reticulon family members which might reflect the morphological changes observed during mitosis (Puhka et al., 2007; Puhka et al., 2012).

Our second major project concerns the creation and maintenance of ER sheets. The maintenance and dynamics of the ER are dependent on functional cytoskeleton composed of microtubules and actin filaments Many structural determinants for tubules and sheets have been identified and the mechanism for tubular movement has been described in detail. Tubules move along the microtubule tracks and play important role in protein transport along the secretory pathway and in ER-organelle contacts. The major ER functions assigned especially to sheets are protein translocation, processing and folding but how the ER sheets are regulated by the cytoskeleton is presently poorly understood.

We have been systematically studying the role of the actin cytoskeleton in the maintenance and dynamics of the sheets. Our studies show that ER sheet dynamics differs from tubular dynamics and propose that actin maintains ER sheet morphology and anchors the sheets in cell periphery to form a stable environment for protein synthesis and quality control.


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