1. Cell Biology
Download icon

Cellular Organisation: Putting organelles in their place

  1. Patricia Ulm
  2. Verena Jantsch  Is a corresponding author
  1. Department of Chromosome Biology, Max Perutz Laboratories, University of Vienna, Vienna Biocenter, Austria
  • Cited 0
  • Views 646
  • Annotations
Cite this article as: eLife 2021;10:e69422 doi: 10.7554/eLife.69422


Experiments in C. elegans reveal new insights into how the ANC-1 protein helps to anchor the nucleus and other organelles in place.

Main text

Cells contain an assortment of organelles which each have their own specialized role. To work correctly, most organelles need to be properly positioned within the cell. For example, mis-localization of the cell’s largest organelle, the nucleus, has been observed in neuromuscular diseases, such as Emery-Dreyfuss muscular dystrophy (Luxton and Starr, 2014).

Current models suggest that positioning of the nucleus relies on a complex called LINC (short for Linker of Nucleoskeleton and Cytoskeleton), which is made up of proteins that contain either a SUN or KASH domain. The SUN proteins (SAD1, UNC-84) sit across the inner nuclear membrane and connect to structures in the nucleus, such as chromatin and the nuclear lamina, and the KASH proteins (Klarsicht, ANC-1, Syne Homology) span across the outer nuclear membrane and interact with proteins in the cytoskeleton. The SUN and KASH domains of these proteins join together to form a bridge that mechanically couples the nucleus and cytoskeleton, which helps to anchor the nucleus in the right place (Kim et al., 2015).

This model of how nuclear positioning works is primarily based on experiments in Caenorhabditis elegans worms with mutations in the genes for either the UNC-84 or ANC-1 protein (Starr and Fridolfsson, 2010). The hypodermis of adult wild-type worms is made up of several huge hyp-7 cells (or syncytia) which each contain 139 evenly spaced nuclei (Shemer and Podbilewicz, 2000), making them a useful system for investigating nuclear anchorage. According to the model, if the nuclei in hyp-7 cells are exclusively anchored via the SUN–KASH bridge, then loss of the genes for UNC-84 or ANC-1 should have an identical effect and result in the same amount of nuclear clustering. However, in 2018, a group of researchers made a puzzling discovery: they found that deleting the gene for ANC-1 resulted in more severe nuclear clustering than removing the gene for UNC-84 (Cain et al., 2018). Now, in eLife, Daniel A Starr and co-workers from University California, Davis – including Hongyan Hao as first author – report that the model for how the nucleus is positioned may need re-defining (Hao et al., 2021).

The team (which includes some of the authors involved in the 2018 study) found, as expected, that removing the gene for ANC-1 led to nuclear clustering in hyp-7 cells, indicating that nuclear anchorage had been lost (Figure 1). The untethered nuclei also disrupted the network of microtubules in the cytoskeleton, and appeared much smaller and less rounded, suggesting that the cells lacked mechanical stability. In C. elegans, the ANC-1 protein contains multiple domains: an actin-binding domain at its N-terminus, several cytoplasmic domains that likely bind to other proteins, a transmembrane domain, and a KASH domain at its C-terminus (Gundersen and Worman, 2013; Starr and Han, 2002). To gain a better understanding of how ANC-1 positions the nucleus, Hao et al. deleted these different domains, either separately or in combination, to see how this affected the protein’s role in the cell.

Loss of ANC-1 leads to unanchored and misshaped organelles and a smaller body size in worms.

The hypodermis of C. elegans worms (top schematic) is made up of hyp-7 cells which contain over a hundred nuclei (represented as black dots). In wild-type worms (left), the KASH protein ANC-1 (depicted as spikes) localizes to the membrane of the nucleus and endoplasmic reticulum (ER). As a result, the nuclei (purple) are spherical and evenly spaced, and the ER (blue), mitochondria (orange) and lipid droplets (yellow) are well anchored. The microtubule network (black lines) is also evenly distributed throughout the cytoplasm. Meanwhile, in mutant worms lacking the gene for ANC-1 (right), the ER and mitochondria are fragmented, and the nuclei are unanchored and clustered together. Lipid droplets are also clustered and the microtubule network is disrupted by the movement of the untethered organelles. This causes the mutant worm to have a smaller body size and the nuclei in its hyp-7 cells to be mispositioned.

Image credit: Patricia Ulm.

Deletion of the KASH domain only caused moderate nuclear clustering, and loss of the actin-binding domain did not generate any nuclear anchorage defects. In contrast, deleting parts of ANC-1 protein that sit within the cytoplasm and likely bind to other cytoskeleton proteins led to more severe positioning defects. Notably, nuclear mispositioning was greatly increased in double mutants lacking both a functional SUN domain in UNC-84 and a cytoplasmic domain of ANC-1. This synergistic effect suggests that nuclear positioning is likely controlled by cooperation between two distinct domains of ANC-1: the cytoplasmic domain and the domain that binds to UNC-84 in the SUN-KASH bridge.

Previous studies have shown that ANC-1 also controls the distribution of mitochondria (Starr and Han, 2002). Therefore, Hao et al. investigated whether ANC-1 is also essential for positioning the mitochondria and another organelle called the endoplasmic reticulum (or ER for short). In mutant worms lacking the gene for ANC-1, they found unanchored fragments of mitochondria and the ER along with clusters of lipid droplets (Figure 1). As seen for the nucleus, deleting the KASH domain only resulted in mild defects in ER positioning, suggesting that localization of the ER also mainly relies on parts of the ANC-1 protein outside the KASH domain.

These findings suggest that ANC-1 positions the nucleus and ER largely independently from the KASH domain. Further experiments revealed that the ANC-1 protein is also located on the membrane of the ER. This led Hao et al. to propose a new cytoplasmic integrity model in which ANC-1 localizes to both the ER and nuclear membranes, and reaches out to correctly position organelles via an interconnecting network that permeates the entire cytoplasm.

This study raises the question of how ANC-1 can position and hold organelles in place with little or no help from its KASH and actin-binding domains. Notably, studies in mice have also shown that the actin-binding domains of Nesprin1 (mouse ANC-1) are not essential to anchor the nucleus within the cytoplasm (Stroud et al., 2017). Therefore, some important questions remain: which cytoskeletal component(s) work with ANC-1 to correctly position organelles and confer mechanical stability to the cell? Are the neuromuscular diseases associated with mutations in the LINC complex the result of alterations in cytoplasmic integrity rather than nuclear anchorage defects? Further experiments using C. elegans as a model system may help to answer these questions and shed further light on how ANC-1 anchors organelles in place.


Article and author information

Author details

  1. Patricia Ulm

    Patricia Ulm is in the Department of Chromosome Biology, Max Perutz Laboratories, University of Vienna, Vienna Biocenter, Vienna, Austria

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8876-2576
  2. Verena Jantsch

    Verena Jantsch is in the Department of Chromosome Biology, Max Perutz Laboratories, University of Vienna, Vienna Biocenter, Vienna, Austria

    For correspondence
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1978-682X

Publication history

  1. Version of Record published: May 21, 2021 (version 1)


© 2021, Ulm and Jantsch

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


  • 646
    Page views
  • 54
  • 0

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cell Biology
    2. Physics of Living Systems
    Jacopo Di Russo et al.
    Research Article

    Nanometer-scale properties of the extracellular matrix influence many biological processes, including cell motility. While much information is available for single-cell migration, to date, no knowledge exists on how the nanoscale presentation of extracellular matrix receptors influences collective cell migration. In wound healing, basal keratinocytes collectively migrate on a fibronectin-rich provisional basement membrane to re-epithelialize the injured skin. Among other receptors, the fibronectin receptor integrin α5β1 plays a pivotal role in this process. Using a highly specific integrin α5β1 peptidomimetic combined with nanopatterned hydrogels, we show that keratinocyte sheets regulate their migration ability at an optimal integrin α5β1 nanospacing. This efficiency relies on the effective propagation of stresses within the cell monolayer independent of substrate stiffness. For the first time, this work highlights the importance of extracellular matrix receptor nanoscale organization required for efficient tissue regeneration.

    1. Cell Biology
    Lisa M Strong et al.
    Research Article Updated

    Autophagy is a cellular process that degrades cytoplasmic cargo by engulfing it in a double-membrane vesicle, known as the autophagosome, and delivering it to the lysosome. The ATG12–5–16L1 complex is responsible for conjugating members of the ubiquitin-like ATG8 protein family to phosphatidylethanolamine in the growing autophagosomal membrane, known as the phagophore. ATG12–5–16L1 is recruited to the phagophore by a subset of the phosphatidylinositol 3-phosphate-binding seven-bladedß -propeller WIPI proteins. We determined the crystal structure of WIPI2d in complex with the WIPI2 interacting region (W2IR) of ATG16L1 comprising residues 207–230 at 1.85 Å resolution. The structure shows that the ATG16L1 W2IR adopts an alpha helical conformation and binds in an electropositive and hydrophobic groove between WIPI2 ß-propeller blades 2 and 3. Mutation of residues at the interface reduces or blocks the recruitment of ATG12–5–16 L1 and the conjugation of the ATG8 protein LC3B to synthetic membranes. Interface mutants show a decrease in starvation-induced autophagy. Comparisons across the four human WIPIs suggest that WIPI1 and 2 belong to a W2IR-binding subclass responsible for localizing ATG12–5–16 L1 and driving ATG8 lipidation, whilst WIPI3 and 4 belong to a second W34IR-binding subclass responsible for localizing ATG2, and so directing lipid supply to the nascent phagophore. The structure provides a framework for understanding the regulatory node connecting two central events in autophagy initiation, the action of the autophagic PI 3-kinase complex on the one hand and ATG8 lipidation on the other.