Coordinated changes in cell membrane and cytoplasm during maturation of apoptotic bleb

Aoki, Kosuke; Satoi, Shinsuke; Harada, Shota; Uchida, Seiichi; Iwasa, Yoh; Ikenouchi, Junichi

doi:10.1091/mbc.e19-12-0691

Cited by 45 publications

(35 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Blebs are hemispherical pressure-driven cellular protrusions that occur when portions of the cell membrane decouple from the actomyosin cortex 6 . Though blebbing famously occurs during apoptosis [26][27][28] , a second class of blebs are found in healthy cells with intact cortices 6,28 . These "dynamic blebs" are associated with cellular detachment, mitosis, and amoeboid motility.…”

Section: Mainmentioning

confidence: 99%

Blebs Promote Cell Survival by Assembling Oncogenic Signaling Hubs

Driscoll

et al. 2021

Preprint

View full text Add to dashboard Cite

For most human cells, anchorage is a key necessity for survival. Cell-substrate adhesion activates diverse signaling pathways, without which cells undergo anoikis – a form of programmed cell death1. Acquisition of anoikis resistance is a pivotal step in cancer disease progression, as metastasizing cancer cells often lose firm attachment to surrounding tissue2–5. In these poorly attached states, cells often adopt rounded morphologies and form small hemispherical plasma membrane protrusions called blebs6–13. Bleb function has long been investigated in the context of amoeboid migration but is far less deeply examined in other scenarios14–19. Here we show by quantitative subcellular 3D imaging and manipulation of cell morphological states that blebbing triggers the formation of membrane-proximal signaling hubs that initiate signaling cascades leading to anoikis resistance. Specifically, in melanoma cells we discovered that blebbing generates plasma membrane contours that recruit curvature sensing septin proteins, which scaffold constitutively active mutant NRAS and effectors, driving the upregulation of ERK and PI3K signaling. Inhibition of blebs or septins has little effect on the survival of well-adhered cells, but in detached cells causes NRAS mislocalization, reduced MAPK and PI3K signaling, and ultimately, death. These data unveil an unanticipated morphological requirement for mutant NRAS to operate as an effective oncoprotein, suggesting novel clinical targets for the treatment of NRAS-driven melanoma. Furthermore, they define an unforeseen role for blebs as potent signaling organelles capable of integrating myriad cellular information flows into concerted signaling responses, in this case granting robust anoikis resistance.Abstract Figure

show abstract

Section: Mainmentioning

confidence: 99%

Blebs Promote Cell Survival by Assembling Oncogenic Signaling Hubs

Driscoll

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The production of ApoEVs is regulated in a dose- and time-dependent manner by different molecular factors, such as the Rho-associated protein kinase (ROCK1) ( Coleman et al, 2001 ; Gregory and Dransfield, 2018 ; Aoki et al, 2020 ) and myosin-light chain kinase (MLCK) ( Mills et al, 1998 ). Inhibitors of ROCK1, MLCK, and caspases can suppress this process.…”

Section: Apoptotic Cell-derived Extracellular Vesiclesmentioning

confidence: 99%

Extracellular Vesicles Derived From Apoptotic Cells: An Essential Link Between Death and Regeneration

Liao

Tian

2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Apoptosis is a universal and continuous event during tissue development, restoration, repair, and regeneration. Mounting evidence has demonstrated that apoptosis is essential for the activation of tissue regeneration. However, the underlying mechanism remains elusive. A striking development in recent years comes from research on extracellular vesicles (EVs) derived from apoptotic cells. During apoptosis, cells secrete vesicles of various sizes containing various components. Apoptotic cell-derived EVs (ApoEVs) have been found to transit to neighboring cells or cells in distant tissues through the circulation. These vesicles could act as containers to transmit the nucleic acid, protein, and lipid signals to target cells. ApoEVs have been shown to promote regeneration in the cardiovascular system, skin, bone, muscle, kidney, etc. Moreover, several specific signaling pathways mediating the anabolic effects of ApoEVs have been classified. In this review, we comprehensively discussed the latest findings on the function of ApoEVs in tissue regeneration and disease prevention. These findings may reveal unexpected clues regarding the regulatory network between cell death and tissue regeneration and suggest novel targets for regenerative medicine. The findings discussed here also raise the question whether and to what extent ApoEVs contribute to embryonic development. This question is all the more urgent because the exact functions of apoptotic events during numerous developmental processes are still largely unclear.

show abstract

“…For instance, caspase-mediated cleavage of the kinase ROCK irreversibly relieves its auto-inhibition. Activated ROCK then mediates phosphorylation of myosin II Regulatory Light Chain (MRLC), causing a hyperactivation of non-muscle myosin II, from which originates the dynamic blebbing of the dying cell membrane, and eventually the formation of the apoptotic bodies [ 12 , 13 , 14 , 15 ]. Interestingly, the inhibition of apoptotic cell contractility through the expression of a non-cleavable form of ROCK has recently been shown to delay the elimination of cell debris, which leads to sterile inflammation and has been associated with tumour suppression [ 16 ].…”

Section: Apoptosis: a Stepwise Dynamic Processmentioning

confidence: 99%

Orchestration of Force Generation and Nuclear Collapse in Apoptotic Cells

Monier

2021

IJMS

View full text Add to dashboard Cite

Apoptosis, or programmed cell death, is a form of cell suicide that is extremely important for ridding the body of cells that are no longer required, to protect the body against hazardous cells, such as cancerous ones, and to promote tissue morphogenesis during animal development. Upon reception of a death stimulus, the doomed cell activates biochemical pathways that eventually converge on the activation of dedicated enzymes, caspases. Numerous pieces of information on the biochemical control of the process have been gathered, from the successive events of caspase activation to the identification of their targets, such as lamins, which constitute the nuclear skeleton. Yet, evidence from multiple systems now shows that apoptosis is also a mechanical process, which may even ultimately impinge on the morphogenesis of the surrounding tissues. This mechanical role relies on dramatic actomyosin cytoskeleton remodelling, and on its coupling with the nucleus before nucleus fragmentation. Here, we provide an overview of apoptosis before describing how apoptotic forces could combine with selective caspase-dependent proteolysis to orchestrate nucleus destruction.

show abstract

Coordinated changes in cell membrane and cytoplasm during maturation of apoptotic bleb

Abstract: In the course of apoptosis, blebs eventually mature into apoptotic bodies that have immune-modulating activities. We clarified changes that occur in the cell membrane during apoptosis, and that those changes are essential for the formation of apoptotic bodies.

Cited by 45 publications

References 31 publications

Blebs Promote Cell Survival by Assembling Oncogenic Signaling Hubs

Blebs Promote Cell Survival by Assembling Oncogenic Signaling Hubs

Extracellular Vesicles Derived From Apoptotic Cells: An Essential Link Between Death and Regeneration

Orchestration of Force Generation and Nuclear Collapse in Apoptotic Cells

Contact Info

Product

Resources

About