Bleb (cell biology)

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During apoptosis, blebbing is the first phase (left) of cell disassembly. Apoptotic cell disassembly.png
During apoptosis, blebbing is the first phase (left) of cell disassembly.

In cell biology, a bleb (or snout) is a bulge of the plasma membrane of a cell, characterized by a spherical, "blister-like", bulky morphology. [2] [3] [4] It is characterized by the decoupling of the cytoskeleton from the plasma membrane, degrading the internal structure of the cell, allowing the flexibility required for the cell to separate into individual bulges or pockets of the intercellular matrix. [4] Most commonly, blebs are seen in apoptosis (programmed cell death) but are also seen in other non-apoptotic functions, including apocrine secretion (cell secretion by disintegration of part of a cell). Blebbing, or zeiosis, is the formation of blebs.

Contents

Formation

Initiation and expansion

Bleb growth is driven by intracellular pressure (abnormal growth) generated in the cytoplasm when the actin cortex undergoes actomyosin contractions. [5] The disruption of the membrane-actin cortex interactions [4] are dependent on the activity of myosin-ATPase [6] Bleb initiation is affected by three main factors: high intracellular pressure, decreased amounts of cortex-membrane linker proteins, and deterioration of the actin cortex. [7] [8] The integrity of the connection between the actin cortex and the membrane are dependent on how intact the cortex is and how many proteins link the two structures. [7] [8] When this integrity is compromised, the addition of pressure is able to make the membrane bulge out from the rest of the cell. [7] [8] The presence of only one or two of these factors is often not enough to drive bleb formation. [8] Bleb formation has also been associated with increases in myosin contractility and local myosin activity increases. [7] [8]

Bleb formation can be initiated in two ways: 1) through local rupture of the cortex or 2) through local detachment of the cortex from the plasma membrane. [9] This generates a weak spot through which the cytoplasm flows, leading to the expansion of the bulge of membrane by increasing the surface area through tearing of the membrane from the cortex, during which time, actin levels decrease. [5] The cytoplasmic flow is driven by hydrostatic pressure inside the cell. [10] [3] Before the bleb is able to expand, pressure must build enough to reach a threshold. [8] This threshold is the amount of pressure needed to overcome the resistance of the plasma membrane to deformation. [8]

Artificial induction

Bleb formation has been artificially induced in multiple lab cell models using different methods. [11] By inserting a micropipette into a cell, the cell can be aspirated rapidly until destruction of cortex-membrane bonds causes blebbing. [11] Breakage of cortex-membrane bonds has also been caused by laser ablation and injection of an actin depolymerizing drug, which in both cases eventually led to blebbing of the cell membrane. [11] Artificially increased levels of myosin contractility were also shown to induce blebbing in cells. [11] Some viruses, such as the poxvirus Vaccinia, have been shown to induce blebbing in cells as they bind to surface proteins. [12] Although the exact mechanism is not yet fully understood, this process is crucial to endocytosing the virion and subsequent infection. [12]

Cellular function

Apoptotic function

Blebbing is one of the defined features of apoptosis. [6] During apoptosis (programmed cell death), the cell's cytoskeleton breaks up and causes the membrane to bulge outward. [13] These bulges may separate from the cell, taking a portion of cytoplasm with them, to become known as apoptotic blebs. [14] Phagocytic cells eventually consume these fragments and the components are recycled.

Two types of blebs are recognized in apoptosis. Initially, small surface blebs are formed. During later stages, larger so-called dynamic blebs may appear, which may carry larger organelle fragments such as larger parts of the fragmented apoptotic cell nucleus. [15]

Function in cell migration

Along with lamellipodia, blebs serve an important role in cell migration. [7] [11] Migrating cells are able to polarize the formation of blebs so blebbing only occurs on the leading edge of the cell. [7] [11] A 2D moving cell is able to use adhesive molecules to gain traction in its environment while blebs form at the leading edge. [7] [11] By forming a bleb, the center of mass of the cell shifts forward and an overall movement of cytoplasm is accomplished. [7] Cells have also been known to accomplish 3D bleb-based movement through a process called chimneying. [7] [11] In this process, cells exert pressure on the top and bottom substrates by squeezing themselves, causing a bleb on the leading edge to grow and the cell to have a net movement forward. [7] [11]

Apocrine secretion

Apocrine secretion is the mode of secretion of exocrine glands wherein secretory cells accumulate material at their apical ends, and this material then buds off from the cells. In many aspects, it can be seen as apoptosis of part of a cell. The secretion process generally initiates with secretory granules accumulating in an apical bleb (also called "apical snout") of the cell, which subsequently disintegrates to release secretory granules into the lumen.

Miscellaneous functions

Blebbing also has important functions in other cellular processes, including cell locomotion, cell division, and physical or chemical stresses. Blebs have been seen in cultured cells in certain stages of the cell cycle. These blebs are used for cell locomotion in embryogenesis. [16] The types of blebs vary greatly, including variations in bleb growth rates, size, contents, and actin content. It also plays an important role in all five varieties of necrosis, a generally detrimental process. However, cell organelles do not spread into necrotic blebs.

Inhibition

Chemical structure of blebbistatin Blebbistatin.png
Chemical structure of blebbistatin

In 2004, a chemical known as blebbistatin was shown to inhibit the formation of blebs. [18] This agent was discovered in a screen for small molecule inhibitors of nonmuscle myosin IIA. [18] Blebbistatin allosterically inhibits myosin II by binding near the actin-binding site and ATP-binding site. [19] This interaction stabilizes a form of myosin II that is not bound to actin, thus lowering the affinity of myosin with actin. [18] [19] [20] [21] By interfering with myosin function, blebbistatin alters the contractile forces that impinge on the cytoskeleton-membrane interface and prevents the build up of intracellular pressure needed for blebbing. [8] [18] [19] [20] [21] Blebbistatin has been investigated for its potential medical uses to treat fibrosis, cancer, and nerve injury. [19] However, blebbistatin is known to be cytotoxic, photosensitive, and fluorescent, leading to the development of new derivatives to solve these problems. [19] Some notable derivatives include azidoblebbistatin, para-nitroblebbistatin, and para-aminoblebbistatin. [19]

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses between 50 and 70 billion cells each day due to apoptosis. For an average human child between eight and fourteen years old, each day the approximate loss is 20 to 30 billion cells.

<span class="mw-page-title-main">Pseudopodia</span> False leg found on slime molds, archaea, protozoans, leukocytes and certain bacteria

A pseudopod or pseudopodium is a temporary arm-like projection of a eukaryotic cell membrane that is emerged in the direction of movement. Filled with cytoplasm, pseudopodia primarily consist of actin filaments and may also contain microtubules and intermediate filaments. Pseudopods are used for motility and ingestion. They are often found in amoebas.

<span class="mw-page-title-main">Microvillus</span> Microscopic protrusion of a cell membrane that increases surface area substantially

Microvilli are microscopic cellular membrane protrusions that increase the surface area for diffusion and minimize any increase in volume, and are involved in a wide variety of functions, including absorption, secretion, cellular adhesion, and mechanotransduction.

<span class="mw-page-title-main">Cytokinesis</span> Part of the cell division process

Cytokinesis is the part of the cell division process and part of mitosis during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of nuclear division in mitosis and meiosis. During cytokinesis the spindle apparatus partitions and transports duplicated chromatids into the cytoplasm of the separating daughter cells. It thereby ensures that chromosome number and complement are maintained from one generation to the next and that, except in special cases, the daughter cells will be functional copies of the parent cell. After the completion of the telophase and cytokinesis, each daughter cell enters the interphase of the cell cycle.

<span class="mw-page-title-main">Cleavage furrow</span> Plasma membrane invagination at the cell division site

In cell biology, the cleavage furrow is the indentation of the cell's surface that begins the progression of cleavage, by which animal and some algal cells undergo cytokinesis, the final splitting of the membrane, in the process of cell division. The same proteins responsible for muscle contraction, actin and myosin, begin the process of forming the cleavage furrow, creating an actomyosin ring. Other cytoskeletal proteins and actin binding proteins are involved in the procedure.

<span class="mw-page-title-main">Actin</span> Family of proteins

Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over 100 μM; its mass is roughly 42 kDa, with a diameter of 4 to 7 nm.

Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations. Cells often migrate in response to specific external signals, including chemical signals and mechanical signals. Errors during this process have serious consequences, including intellectual disability, vascular disease, tumor formation and metastasis. An understanding of the mechanism by which cells migrate may lead to the development of novel therapeutic strategies for controlling, for example, invasive tumour cells.

<span class="mw-page-title-main">Cell cortex</span> Layer on the inner face of a cell membrane

The cell cortex, also known as the actin cortex, cortical cytoskeleton or actomyosin cortex, is a specialized layer of cytoplasmic proteins on the inner face of the cell membrane. It functions as a modulator of membrane behavior and cell surface properties. In most eukaryotic cells lacking a cell wall, the cortex is an actin-rich network consisting of F-actin filaments, myosin motors, and actin-binding proteins. The actomyosin cortex is attached to the cell membrane via membrane-anchoring proteins called ERM proteins that plays a central role in cell shape control. The protein constituents of the cortex undergo rapid turnover, making the cortex both mechanically rigid and highly plastic, two properties essential to its function. In most cases, the cortex is in the range of 100 to 1000 nanometers thick.

<span class="mw-page-title-main">Protein filament</span> Long chain of protein monomers

In biology, a protein filament is a long chain of protein monomers, such as those found in hair, muscle, or in flagella. Protein filaments form together to make the cytoskeleton of the cell. They are often bundled together to provide support, strength, and rigidity to the cell. When the filaments are packed up together, they are able to form three different cellular parts. The three major classes of protein filaments that make up the cytoskeleton include: actin filaments, microtubules and intermediate filaments.

Entosis is the invasion of a living cell into another cell's cytoplasm. The process was discovered by Overholtzer et al. as reported in Cell.

<span class="mw-page-title-main">MYH10</span> Protein-coding gene in the species Homo sapiens

Myosin-10 also known as myosin heavy chain 10 or non-muscle myosin IIB (NM-IIB) is a protein that in humans is encoded by the MYH10 gene. Non-muscle myosins are expressed in a wide variety of tissues, but NM-IIB is the only non-muscle myosin II isoform expressed in cardiac muscle, where it localizes to adherens junctions within intercalated discs. NM-IIB is essential for normal development of cardiac muscle and for integrity of intercalated discs. Mutations in MYH10 have been identified in patients with left atrial enlargement.

<span class="mw-page-title-main">ANLN</span> Mammalian protein found in Homo sapiens

Anillin is a conserved protein implicated in cytoskeletal dynamics during cellularization and cytokinesis. The ANLN gene in humans and the scraps gene in Drosophila encode Anillin. In 1989, anillin was first isolated in embryos of Drosophila melanogaster. It was identified as an F-actin binding protein. Six years later, the anillin gene was cloned from cDNA originating from a Drosophila ovary. Staining with anti-anillin antibody showed the anillin localizes to the nucleus during interphase and to the contractile ring during cytokinesis. These observations agree with further research that found anillin in high concentrations near the cleavage furrow coinciding with RhoA, a key regulator of contractile ring formation.

<span class="mw-page-title-main">Amoeboid movement</span> Mode of locomotion in eukaryotic cells

Amoeboid movement is the most typical mode of locomotion in adherent eukaryotic cells. It is a crawling-like type of movement accomplished by protrusion of cytoplasm of the cell involving the formation of pseudopodia ("false-feet") and posterior uropods. One or more pseudopodia may be produced at a time depending on the organism, but all amoeboid movement is characterized by the movement of organisms with an amorphous form that possess no set motility structures.

<span class="mw-page-title-main">Rho-associated protein kinase</span>

Rho-associated protein kinase (ROCK) is a kinase belonging to the AGC family of serine-threonine specific protein kinases. It is involved mainly in regulating the shape and movement of cells by acting on the cytoskeleton.

<span class="mw-page-title-main">ADAM7</span> Protein-coding gene in the species Homo sapiens

Disintegrin and metalloproteinase domain-containing protein 7 is a protein that in humans is encoded by the ADAM7 gene. ADAM7 is an 85-kDa enzyme that is a member of the transmembrane ADAM protein family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. ADAM7 is important for the maturation of sperm cells in mammals. ADAM7 is also denoted as: ADAM_7, ADAM-7, EAPI, GP-83, and GP83.

<span class="mw-page-title-main">RMDN3</span> Protein-coding gene in the species Homo sapiens

Regulator of microtubule dynamics protein 3 (RMDN3), more commonly known as Protein tyrosine phosphatase interacting protein 51 (PTPIP51), is a protein that in humans is encoded by the RMDN3 gene on chromosome 15. This protein contributes to multiple biological functions, including cellular differentiation, proliferation, motility, cytoskeleton formation, and apoptosis, and has been associated with numerous cancers.

<span class="mw-page-title-main">Blebbistatin</span> Chemical compound

Blebbistatin is a myosin inhibitor mostly specific for myosin II. It is widely used in research to inhibit heart muscle myosin, non-muscle myosin II, and skeletal muscle myosin. Blebbistatin has been especially useful in optical mapping of the heart, and its recent use in cardiac muscle cell cultures has improved cell survival time. However, its adverse characteristics e.g. its cytotoxicity and blue-light instability or low solubility in water often make its application challenging. Recently its applicability was improved by chemical design and its derivatives overcome the limitations of blebbistatin. E.g. para-nitroblebbistatin and para-aminoblebbistatin are photostable, and they are neither cytotoxic nor fluorescent.

<span class="mw-page-title-main">Actomyosin ring</span> Cellular formation during cytokinesis

In molecular biology, an actomyosin ring or contractile ring, is a prominent structure during cytokinesis. It forms perpendicular to the axis of the spindle apparatus towards the end of telophase, in which sister chromatids are identically separated at the opposite sides of the spindle forming nuclei. The actomyosin ring follows an orderly sequence of events: identification of the active division site, formation of the ring, constriction of the ring, and disassembly of the ring. It is composed of actin and myosin II bundles, thus the term actomyosin. The actomyosin ring operates in contractile motion, although the mechanism on how or what triggers the constriction is still an evolving topic. Other cytoskeletal proteins are also involved in maintaining the stability of the ring and driving its constriction. Apart from cytokinesis, in which the ring constricts as the cells divide, actomyosin ring constriction has also been found to activate during wound closure. During this process, actin filaments are degraded, preserving the thickness of the ring. After cytokinesis is complete, one of the two daughter cells inherits a remnant known as the midbody ring.

Ewa Paluch is a French-Polish biophysicist and cell biologist. She is the 17th Professor of Anatomy in the Department of Physiology, Development and Neuroscience and Fellow of Trinity College at the University of Cambridge.

<span class="mw-page-title-main">Cell extrusion</span> Process in cell biology

Cell extrusion, discovered in 2001, is a process conserved in epithelial from humans to sea sponge to seamlessly remove unwanted or dying cells while maintaining the integrity of the epithelial barrier. If cells were to die without extrusion, gaps would be created, compromising the epithelia's function. While cell targeted to die by apoptotic stimuli extrude to prevent gaps from forming, most cells die as a result of extruding live cells. To maintain epithelial cell number homeostasis, live cells extrude when they become too crowded.

References

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