JCB biowrites

JCB unveils new website

The JCB is proud to unveil a new and improved website today as part of the site redesign by the Rockefeller University Press (RUP). The site has an updated look and functionality to better present and highlight new research.

You can read more about the features of the new site in an Editorial by RUP Executive Director Mike Rossner.

We hope that you find the updated navigation and design to be useful. We would be grateful for any feedback you have, which can be provided by clicking the feedback link in the bottom navigation links on the JCB pages.

New issue: March 22nd

The latest issue of the JCB is out today. You can find the table of contents here, but here's a quick rundown of some of the issue's highlights...

Attachments between kinetochores and spindle microtubules are regulated by the aurora B kinase, which eliminates incorrect attachments by phosphorylating kinetochore proteins to reduce their microtubule-binding capacity . (Our cover image shows the mis-attachments that result when aurora B is inhibited.) But the kinase's activity must be reversed by a phosphatase to stabilize correct kinetochore-microtubule connections. Liu et al. report that Protein Phosphatase I (PPI) is responsible for this stabilization, and that it is recruited to kinetochores by binding to the protein KNL1. PPI's association with KNL1 is inhibited by aurora B until - the authors propose - correct microtubule attachments generate tension that pulls KNL1 out of aurora B's reach, allowing PPI to bind and stabilize the attachments. Senior author Michael Lampson explains here how this mechanism could involve a feedback loop that helps sharpen the transition between strong and weak microtubule binding. Meanwhile, Kiyomitsu et al. demonstrate how the kinetochore protein hMis14 works with the heterochromatin protein HP1 to build the inner centromere structure that links sister kinetochores during mitosis.

Our "In Focus" article this issue highlights a fascinating paper from Okreglak and Drubin that reveals that actin filaments can be constructed from short actin oligomers rather than exclusively from actin monomers. David Drubin tells me here that they made this surprising discovery when they continued to see actin polymerization at yeast endocytic sites in the presence of the monomer-sequestering drug latrunculin A. The short oligomers in question seem to be produced by the actin severing protein cofilin as it disassembles older filaments. Moreover, Okreglak and Drubin show that the cofilin accessory protein Aip1p completely breaks down the short oligomers into monomers and that oligomer-driven filament assembly is thus enhanced in cells lacking Aip1p. Drubin says it remains to be seen if actin filaments at other cellular sites are constructed from oligomers as well as monomers.

Elsewhere, Mittal et al. describe how that TNF-related cytokine TWEAK induces the wasting of skeletal muscle when it's disused (after loss of innervation, for example). The researchers found that TWEAK's receptor, Fn14, is upregulated when muscle is denervated, allowing TWEAK to activate the transcription factor NFkappaB. This drives expression of the ubiquitin ligase MuRF-1, which targets components of the muscle thick filaments for degradation. As I explain in this summary, the pathway may be a viable therapeutic target to prevent muscle atrophy in patients whose muscle usage is curtailed.

From skeletal muscle to the pancreas: Zito et al. report that the endoplasmic reticulum oxidoreductase ERO1-beta, which helps secretory proteins fold by promoting disulphide bond formation, has a surprisingly selective substrate in the form of proinsulin. Mice lacking ERO1-beta develop glucose intolerance (despite the presence of another isoform of the enzyme, ERO1-alpha). Carolyn Sevier puts the data into context in her accompanying commentary.

Onto the vasculature next, as Cain et al. reveal how the phosphatidylinositol-3-kinase subunit p110alpha increases endothelial permeability in response to TNFalpha. p110alpha (and not any other isoforms of the enzyme) regulates the tyrosine kinase Pyk2 and the small GTPase Rac at endothelial cell junctions. The image to the left shows that cells lacking p110alpha (right) maintain their junctions after TNFalpha treatment, unlike control cells (left).

Meanwhile, Herkert et al. demonstrate that cell adhesion (both to each other and to the cell matrix) is globally inhibited by the tumor suppressors Arf and Miz1. Separately, both of these proteins can induce cell cycle arrest in response to a variety of stresses. However, in combination, Arf and Miz1 repress numerous cell adhesion genes and induce apoptosis. This might be a mechanism for tissues to eliminate cells with potentially oncogenic mutations, says senior author Martin Eilers. You can read a longer summary here, including a description of how Myc may switch Arf from arresting damaged cells to killing them. This issue also features a review by Ruoslahti et al., that describes how tumors may be therapeutically targeted using drug conjugates and nanoparticles that specifically dock on cell surface proteins that are highly expressed in the tumor's vasculature.

You can find plenty of other interesting papers in this issue's table of contents, but I'll leave you today with our latest biosights video podcast, which this month features Martin et al.'s description of the integration of contractile forces across whole tissues during epithelial morphogenesis. If you missed the paper in the previous issue of the JCB, you can hear lead author Adam Martin describe his experiments and watch the spectacular movies he took of Drosophila embryos tearing apart when tissue tension is disrupted:

New issue: March 8th

It's a little later than usual, but here's a roundup what you can find in the latest issue of the JCB...

Our spectacular cover image shows the epithelial cells of a Drosophila embryo torn apart when they lack armadillo - the fly homolog of the adherens junction component beta-catenin. The picture is taken from the paper by Martin et al., who show that these epithelial tears arise because adherens junctions are critical for integrating the contractile forces generated by individual cells across the tissue. The junctions connect cellular actomyosin fibers into a supracellular meshwork that generates tension across the epithelial sheet as it undergoes a morphogenetic movement called mesoderm invagination. The transcription factor Twist is also required to stabilize this meshwork. The tension is predominantly along the embryo's anterior-posterior axis which, as you can read in Mitch's summary, explains why the epithelial cells change shape as they constrict, to drive the tissue's invagination.

Elsewhere, Januschke and Gonzalez reveal how centrosomes and interphase microtubules combine to ensure Drosophila neuroblast stem cells always divide with the same orientation to produce daughter cells with distinct developmental fates. The centrosomes and microtubules mark the apical side of a dividing neuroblast and remember this position throughout the following interphase so that the apical side forms in the same place during the next division. Mitch wrote this month's In Focus article about the paper, where you can read how the authors used the drug colcemid to disrupt microtubules at different points in the cell cycle to investigate their function in remembering the stem cell's orientation. Meanwhile Suetterlin and Colanzi review how the centrosome performs many of its functions in conjunction with the Golgi apparatus. The two organelles are closely associated in interphase cells and, recent evidence suggests, work together in cell polarization and oriented protein secretion.

 Mukhopadhyay et al. describe how a protein that shortens chains of SUMO molecules is essential to kinetochore assembly. SENP6 is a protease that cleaves SUMO molecules off of the kinetochore component CENP-I. This prevents the ubiquitin ligase RNF4 from recognizing SUMO-tagged CENP-I and targeting it to the proteasome for degradation. In SENP6's absence, CENP-I degradation is accelerated such that it isn't incorporated into kinetochores, resulting in spindle assembly and mitotic defects. Mitch's summary of the paper is here. Meanwhile Jaqaman et al. develop a live cell imaging system to analyze the dynamics of sister kinetochores as they align at the metaphase plate (see the images to the right). They find that alignment is regulated by the stiffness of the physical links between sister kinetochores, and by microtubule depolymerases.

Finally for today, Kim et al. investigate a previously-uncharacterized Drosophila protein that they name ema, as it turns out to be involved in endosome maturation - the process by which early endosomes develop into late endosomes and then into degradative lysosomes. Flies lacking ema have overgrown neuromuscular junctions because they can't downregulate BMP signaling by destroying the BMP receptor. The human homolog of ema is linked to autoimmune disorders - you can hear lead author Aaron DiAntonio discuss what this might have to do with endosome maturation and describe the rest of his group's findings in this month's biobytes podcast. You can also hear Luisa Iruela-Arispe explain how the context of the extracellular matrix determines an endothelial cell's response to VEGF (or see the paper by Chen et al. from the previous issue of the JCB). Listen in the player below, or subscribe via iTunes. And you can find lot's of other great papers in the latest issue's table of contents by clicking here.

Cilium formation: Lessons from the past

I recently attended a Keystone Symposium on Cilia, Signaling and Human Disease.  It was an excellent meeting with a wide range of participants who remained engaged in the presentations throughout the conference.  Several of the talks showed EM images from a JCB paper published in 1962.  This made me curious about the article and I decided to investigate. 

The paper “Centrioles and the formation of rudimentary cilia by fibroblasts and smooth muscle cells” is from Sergei Sorokin.  Using EM, the study documents cilia formation in these cells types isolated from the chick and the rat or from chick organ cultures.  From his observations, Sorokin divided cilia formation into three phases. 

In the first phase (“Centriole, primary vesicle and ciliary bud”), he observed that the appearance of a single vesicle (called the primary vesicle) at the end of one of the centrioles is the earliest marker of cilium formation (Left).  After attachment of the vesicle to the end of the centriole, electron dense material becomes deposited at the end of the centriole abutting the vesicle (termed the ‘ciliary bud’) causing the vesicle to become ‘mushroom’ shaped.  All of this occurs with the centrosome still adjacent to the nucleus.  So, at least in these cell types, the formation of the cilia does not require movement of the centrosome to the surface of the cell. 

In the second phase (“Development of the shaft and sheath of the cilium”), he observed that the shaft is an elongation of the ciliary bud (Left).  The sheath appears to form by the fusion of additional ciliary vesicles with the primary vesicle. 

Phase three (“Emergence and internal development of the cilium”) starts once the  shaft and sheath of the cilium have reached the cell surface.  In this phase, the sheath membranes fuse with the plasma membrane and the cilium protrudes out of the cell (Right).

My brief summary does not do this paper justice.  The EM images are absolutely amazing and I urge anyone who is interested to look at the original paper.  Although we know much more about the function of cilia and many components of these enigmatic organelles have been identified, the molecular details underlying cilia formation are still largely a mystery.  Many labs are hard at work to decipher this process but one can easily see why this early study from 1962 provides a nice framework with which to think about this process.

This was the first iteration of this meeting but I have no doubt that it will become a recurring event.  At the next conference, I imagine that the field will have a better handle on the molecular mechanisms underlying the formation of this fascinating organelle.

S. Sorokin. J. Cell Biol., Nov 1962; 15: 363 - 377.