Ferroptosis is a regulated form of necrotic cell death that is caused by the accumulation of oxidized phospholipids, leading to membrane damage and cell lysis
1
,
2
. While other types of necrotic death such as pyroptosis and necroptosis are mediated by active mechanisms of execution
3
–
6
, ferroptosis is thought to result from the accumulation of unrepaired cell damage
1
. Previous studies suggested that ferroptosis has the ability to spread through cell populations in a wave-like manner, resulting in a distinct spatiotemporal pattern of cell death
7
,
8
. Here we investigate the mechanism of ferroptosis execution and discover that ferroptotic cell rupture is mediated by plasma membrane pores, similarly to cell lysis in pyroptosis and necroptosis
3
,
4
. We further find that intercellular propagation of death occurs following treatment with some ferroptosis-inducing agents, including erastin
2
,
9
and C’ dot nanoparticles
8
, but not upon direct inhibition of the ferroptosis-inhibiting enzyme Glutathione Peroxidase 4 (GPX4)
10
. Propagation of a ferroptosis-inducing signal occurs upstream of cell rupture, and involves the spreading of a cell swelling effect through cell populations in a lipid peroxide- and iron-dependent manner.
SUMMARY
Increased expression of vimentin intermediate filaments (VIF) enhances
directed cell migration, but the mechanism behind VIF’s effect on
motility is not understood. VIF interact with microtubules, whose organization
contributes to polarity maintenance in migrating cells. Here we characterize the
dynamic coordination of VIF and microtubule networks in wounded monolayers of
Retinal Pigment Epithelial cells. By genome editing we fluorescently labelled
endogenous vimentin and α-tubulin and we developed computational image
analysis to delineate architecture and interactions of the two networks. Our
results show that VIF assemble an ultrastructural copy of the previously
polarized microtubule network. Because the VIF network is long-lived compared to
the microtubule network, VIF template future microtubule growth along previous
microtubule tracks, thus providing a feedback mechanism that maintains cell
polarity. VIF knockdown prevents cells from polarizing and migrating properly
during wound healing. We suggest that VIF’s templating function
establishes a memory in microtubule organization that enhances persistence in
cell polarization in general and migration in particular.
This work identified a cycle of actin assembly and disassembly in large secretory vesicles of Drosophila salivary glands. Actin disassembly is triggered by actin-dependent recruitment of a RhoGAP protein and is essential for the contractility of the vesicle, leading to content release to the lumen.
Summary
Myoblast fusion is essential for muscle development and regeneration. Yet, it remains poorly understood how mononucleated myoblasts fuse with preexisting fibers. We demonstrate that ERK1/2 inhibition (ERKi) induces robust differentiation and fusion of primary mouse myoblasts through a linear pathway involving RXR, ryanodine receptors, and calcium-dependent activation of CaMKII in nascent myotubes. CaMKII activation results in myotube growth via fusion with mononucleated myoblasts at a fusogenic synapse. Mechanistically, CaMKII interacts with and regulates MYMK and Rac1, and CaMKIIδ/γ knockout mice exhibit smaller regenerated myofibers following injury. In addition, the expression of a dominant negative CaMKII inhibits the formation of large multinucleated myotubes. Finally, we demonstrate the evolutionary conservation of the pathway in chicken myoblasts. We conclude that ERK1/2 represses a signaling cascade leading to CaMKII-mediated fusion of myoblasts to myotubes, providing an attractive target for the cultivated meat industry and regenerative medicine.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.