Cell-cell fusion: To lose one life and begin another.

As life extended into eukaryota, a great host of strategies emerged in the pursuit of cellular life. Some cells have been successful in solitude, some moved into cooperatives (i.e.

FORMATION OF MULTINUCLEATED OSTEOCLASTS DEPENDS ON AN OXIDIZED SPECIES OF CELL SURFACE ASSOCIATED LA PROTEIN.

The bone-resorbing activity of osteoclasts plays a critical role in the life-long remodeling of our bones that is perturbed in many bone loss diseases. Multinucleated osteoclasts are formed by the fusion of precursor cells, and larger cells - generated by an increased number of cell fusion events - have higher resorptive activity. We find that osteoclast fusion and bone-resorption are promoted by reactive oxygen species (ROS) signaling and by an unconventional low molecular weight species of La protein, located at the osteoclast surface.

RANKL inhibition reduces lesional cellularity and Gα variant expression and enables osteogenic maturation in fibrous dysplasia.

Fibrous dysplasia (FD) is a rare, disabling skeletal disease for which there are no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre- and post-treatment in a phase 2 clinical trial of denosumab (NCT03571191) and in murine in vivo and ex vivo preclinical models.

Muscle Progenitor Cell Fusion in the Maintenance of Skeletal Muscle.

Skeletal muscle possesses a resident, multipotent stem cell population that is essential for its repair and maintenance throughout life. Here I highlight the role of this stem cell population in muscle repair and regeneration and review the genetic control of the process; the mechanistic steps of activation, migration, recognition, adhesion, and fusion of these cells; and discuss the novel recognition of the membrane signaling that coordinates myogenic cell-cell fusion, as well as the identification of a two-part fusogen system that facilitates it.

An inducible explant model of osteoclast-osteoprogenitor coordination in exacerbated osteoclastogenesis.

Elucidating a basic blueprint of osteoclast-osteoblast coordination in skeletal remodeling and understanding how this coordination breaks down with age and disease is essential for addressing the growing skeletal health problem in our aging population. The paucity of simple, activatable, biologically relevant models of osteoclast-osteoblast coordination has hindered our understanding of how skeletal remolding is regulated. Here, we describe an inducible model of osteoclast-osteoblast progenitor coordination.

Cell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis.

Multinucleated osteoclasts, essential for skeletal remodeling in health and disease, are formed by the fusion of osteoclast precursors, where each fusion event raises their bone-resorbing activity. Here we show that the nuclear RNA chaperone, La protein has an additional function as an osteoclast fusion regulator. Monocyte-to-osteoclast differentiation starts with a drastic decrease in La levels.

IL-27 Modulates the Cytokine Secretion in the T Cell-Osteoclast Crosstalk During HIV Infection.

In People with HIV (PWH), chronic immune activation and systemic inflammation are associated with increased risk to develop comorbidities including bone loss. Numerous cells of the immune system, namely, T cells are involved in the regulation of the bone homeostasis and osteoclasts (OCs) activity. IL-27, a cytokine that belongs to the IL-12 family can regulate the secretion of pro- and anti-inflammatory cytokines by T cells, however its role in the setting of HIV is largely unknown.

The taming of a scramblase.

Intracellular pH joins the regulatory apparatus of the TMEM16 scramblase module.

Flagging fusion: Phosphatidylserine signaling in cell-cell fusion.

Formations of myofibers, osteoclasts, syncytiotrophoblasts, and fertilized zygotes share a common step, cell-cell fusion. Recent years have brought about considerable progress in identifying some of the proteins involved in these and other cell-fusion processes. However, even for the best-characterized cell fusions, we still do not know the mechanisms that regulate the timing of cell-fusion events.

Myomerger promotes fusion pore by elastic coupling between proximal membrane leaflets and hemifusion diaphragm.

Myomerger is a muscle-specific membrane protein involved in formation of multinucleated muscle cells by mediating the transition from the early hemifusion stage to complete fusion. Here, we considered the physical mechanism of the Myomerger action based on the hypothesis that Myomerger shifts the spontaneous curvature of the outer membrane leaflets to more positive values. We predicted, theoretically, that Myomerger generates the outer leaflet elastic stresses, which propagate into the hemifusion diaphragm and accelerate the fusion pore formation.

Anoctamin 5/TMEM16E facilitates muscle precursor cell fusion.

Limb-girdle muscular dystrophy type 2L (LGMD2L) is a myopathy arising from mutations in ; however, information about the contribution of ANO5 to muscle physiology is lacking. To explain the role of ANO5 in LGMD2L, we previously hypothesized that ANO5-mediated phospholipid scrambling facilitates cell-cell fusion of mononucleated muscle progenitor cells (MPCs), which is required for muscle repair. Here, we show that heterologous overexpression of ANO5 confers Ca-dependent phospholipid scrambling to HEK-293 cells and that scrambling is associated with the simultaneous development of a nonselective ionic current.

Anoctamins/TMEM16 Proteins: Chloride Channels Flirting with Lipids and Extracellular Vesicles.

Anoctamin (ANO)/TMEM16 proteins exhibit diverse functions in cells throughout the body and are implicated in several human diseases. Although the founding members ANO1 (TMEM16A) and ANO2 (TMEM16B) are Ca-activated Cl channels, most ANO paralogs are Ca-dependent phospholipid scramblases that serve as channels facilitating the movement (scrambling) of phospholipids between leaflets of the membrane bilayer. Phospholipid scrambling significantly alters the physical properties of the membrane and its landscape and has vast downstream signaling consequences.

Defective membrane fusion and repair in Anoctamin5-deficient muscular dystrophy.

Limb-girdle muscular dystrophies are a genetically diverse group of diseases characterized by chronic muscle wasting and weakness. Recessive mutations in ANO5 (TMEM16E) have been directly linked to several clinical phenotypes including limb-girdle muscular dystrophy type 2L and Miyoshi myopathy type 3, although the pathogenic mechanism has remained elusive. ANO5 is a member of the Anoctamin/TMEM16 superfamily that encodes both ion channels and regulators of membrane phospholipid scrambling.

A Pore Idea: the ion conduction pathway of TMEM16/ANO proteins is composed partly of lipid.

Since their first descriptions, ion channels have been conceived as proteinaceous conduits that facilitate the passage of ionic cargo between segregated environments. This concept is reinforced by crystallographic structures of cation channels depicting ion conductance pathways completely lined by protein. Although lipids are sometimes present in fenestrations near the pore or may be involved in channel gating, there is little or no evidence that lipids inhabit the ion conduction pathway.

Identification of a lipid scrambling domain in ANO6/TMEM16F.

Phospholipid scrambling (PLS) is a ubiquitous cellular mechanism involving the regulated bidirectional transport of phospholipids down their concentration gradient between membrane leaflets. ANO6/TMEM16F has been shown to be essential for Ca(2+)-dependent PLS, but controversy surrounds whether ANO6 is a phospholipid scramblase or an ion channel like other ANO/TMEM16 family members. Combining patch clamp recording with measurement of PLS, we show that ANO6 elicits robust Ca(2+)-dependent PLS coinciding with ionic currents that are explained by ionic leak during phospholipid translocation.