Multiple roles of CD90 in cancer.

THY1 (CD90) is a 25-37-kDa heavily N-glycosylated, glycophosphatidylinositol (GPI) anchored cell surface protein. It is usually expressed on thymocytes, mesenchymal stem cells, hematopoietic stem cells, natural killer cells, neurons, endothelial cells, renal glomerular mesangial cells, follicular dendritic cells, fibroblasts, and myofibroblasts. It has been found to regulate cell adhesion, migration, apoptosis, axon growth, cell-cell and cell-matrix interactions, T-cell activation, and fibrosis. Several reports have shown that CD90 has an important role in cancer in regulating cancer cell proliferation, metastasis, and angiogenesis. There are also evidences that CD90 is an important prognostic marker in many cancers. Consequently, therapies that target CD90 have great promise in treating many cancers. However, several studies also indicate a contradictory role for CD90, where it acts as a tumor suppressor. In this review, we summarize the expression, function of CD90 in different cancers and its possible use as a biomarker or a therapeutic target in cancer. The challenges and future prospects for the use of CD90 for clinical applications are also discussed in this review.

N-WASP-dependent branched actin polymerization attenuates B-cell receptor signaling by increasing the molecular density of receptor clusters.

Antigen-induced B-cell receptor (BCR) signaling is critical for initiating and regulating B-cell activation. The actin cytoskeleton plays essential roles in BCR signaling. Upon encountering cell-surface antigens, actin-driven B-cell spreading amplifies signaling, while B-cell contraction following spreading leads to signal attenuation. However, the mechanism by which actin dynamics switch BCR signaling from amplification to attenuation is unknown. Here, we show that Arp2/3-mediated branched actin polymerization is required for mouse splenic B-cell contraction. Contracting B-cells generate centripetally moving actin foci from lamellipodial F-actin networks in the plasma membrane region contacting antigen-presenting surfaces. Actin polymerization driven by N-WASP, but not WASP, initiates these actin foci and facilitates non-muscle myosin II recruitment to the contact zone, creating actomyosin ring-like structures. B-cell contraction increases BCR molecular density in individual clusters, leading to decreased BCR phosphorylation. Increased BCR molecular density reduced levels of the stimulatory kinase Syk, the inhibitory phosphatase SHIP-1, and their phosphorylated forms in individual BCR clusters. These results suggest that N-WASP-activated Arp2/3, coordinating with myosin, generates centripetally moving foci and contractile actomyosin ring-like structures from lamellipodial networks, enabling contraction. B-cell contraction attenuates BCR signaling by pushing out both stimulatory kinases and inhibitory phosphatases from BCR clusters, providing novel insights into actin-facilitated signal attenuation.

N-WASP-dependent branched actin polymerization attenuates B-cell receptor signaling by increasing the molecular density of receptor clusters.

Antigen-induced B-cell receptor (BCR) signaling is critical for initiating and regulating B-cell activation. The actin cytoskeleton plays essential roles in BCR signaling. Upon encountering cell-surface antigens, actin-driven B-cell spreading amplifies signaling, while B-cell contraction following spreading leads to signal attenuation. However, the mechanism by which actin dynamics switch BCR signaling from amplification to attenuation is unknown. Here, we show that Arp2/3-mediated branched actin polymerization is required for B-cell contraction. Contracting B-cells generate centripetally moving actin foci from lamellipodial F-actin networks in the B-cell plasma membrane region contacting antigen-presenting surfaces. Actin polymerization driven by N-WASP, but not WASP, initiates these actin foci and facilitates non-muscle myosin II recruitment to the contact zone, creating actomyosin ring-like structures. Furthermore, B-cell contraction increases BCR molecular density in individual clusters, leading to decreased BCR phosphorylation. Increased BCR molecular density reduced levels of the stimulatory kinase Syk, the inhibitory phosphatase SHIP-1, and their phosphorylated forms in individual BCR clusters. These results suggest that N-WASP-activated Arp2/3, coordinating with myosin, generates centripetally moving foci and contractile actomyosin ring-like structures from lamellipodial networks, enabling contraction. B-cell contraction attenuates BCR signaling by pushing out both stimulatory kinases and inhibitory phosphatases from BCR clusters, providing novel insights into actin-facilitated signal attenuation.

Bidirectional feedback between BCR signaling and actin cytoskeletal dynamics.

When B cells are exposed to antigens, they use their B-cell receptors (BCRs) to transduce this external signal into internal signaling cascades and uptake antigen, which activate transcriptional programs. Signaling activation requires complex cytoskeletal remodeling initiated by BCR signaling. The actin cytoskeletal remodeling drives B-cell morphological changes, such as spreading, protrusion, contraction, and endocytosis of antigen by mechanical forces, which in turn affect BCR signaling. Therefore, the relationship between the actin cytoskeleton and BCR signaling is a two-way feedback loop. These morphological changes represent the indirect ways by which the actin cytoskeleton regulates BCR signaling. Recent studies using high spatiotemporal resolution microscopy techniques have revealed that actin also can directly influence BCR signaling. Cortical actin networks directly affect BCR mobility, not only during the resting stage by serving as diffusion barriers, but also at the activation stage by altering BCR diffusivity through enhanced actin flow velocities. Furthermore, the actin cytoskeleton, along with myosin, enables B cells to sense the physical properties of its environment and generate and transmit forces through the BCR. Consequently, the actin cytoskeleton modulates the signaling threshold of BCR to antigenic stimulation. This review discusses the latest research on the relationship between BCR signaling and actin remodeling, and the research techniques. Exploration of the role of actin in BCR signaling will expand fundamental understanding of the relationship between cell signaling and the cytoskeleton and the mechanisms underlying cytoskeleton-related immune disorders and cancer.

Corrigendum: WASp Is Crucial for the Unique Architecture of the Immunological Synapse in Germinal Center B-Cells.

[This corrects the article DOI: 10.3389/fcell.2021.646077.].

WASp Is Crucial for the Unique Architecture of the Immunological Synapse in Germinal Center B-Cells.

B-cells undergo somatic hypermutation and affinity maturation in germinal centers. Somatic hypermutated germinal center B-cells (GCBs) compete to engage with and capture antigens on follicular dendritic cells. Recent studies show that when encountering membrane antigens, GCBs generate actin-rich pod-like structures with B-cell receptor (BCR) microclusters to facilitate affinity discrimination. While deficiencies in actin regulators, including the Wiskott-Aldrich syndrome protein (WASp), cause B-cell affinity maturation defects, the mechanism by which actin regulates BCR signaling in GBCs is not fully understood. Using WASp knockout (WKO) mice that express Lifeact-GFP and live-cell total internal reflection fluorescence imaging, this study examined the role of WASp-mediated branched actin polymerization in the GCB immunological synapse. After rapid spreading on antigen-coated planar lipid bilayers, GCBs formed microclusters of phosphorylated BCRs and proximal signaling molecules at the center and the outer edge of the contact zone. The centralized signaling clusters localized at actin-rich GCB membrane protrusions. WKO reduced the centralized micro-signaling clusters by decreasing the number and stability of F-actin foci supporting GCB membrane protrusions. The actin structures that support the spreading membrane also appeared less frequently and regularly in WKO than in WT GCBs, which led to reductions in both the level and rate of GCB spreading and antigen gathering. Our results reveal essential roles for WASp in the generation and maintenance of unique structures for GCB immunological synapses.

WASP family proteins regulate the mobility of the B cell receptor during signaling activation.

Regulation of membrane receptor mobility tunes cellular response to external signals, such as in binding of B cell receptors (BCR) to antigen, which initiates signaling. However, whether BCR signaling is regulated by BCR mobility, and what factors mediate this regulation, are not well understood. Here we use single molecule imaging to examine BCR movement during signaling activation and a novel machine learning method to classify BCR trajectories into distinct diffusive states. Inhibition of actin dynamics downstream of the actin nucleating factors, Arp2/3 and formin, decreases BCR mobility. Constitutive loss or acute inhibition of the Arp2/3 regulator, N-WASP, which is associated with enhanced signaling, increases the proportion of BCR trajectories with lower diffusivity. Furthermore, loss of N-WASP reduces the diffusivity of CD19, a stimulatory co-receptor, but not that of FcγRIIB, an inhibitory co-receptor. Our results implicate a dynamic actin network in fine-tuning receptor mobility and receptor-ligand interactions for modulating B cell signaling.

Comparative Studies of Oleaginous Fungal Strains (Mucor circinelloides and Trichoderma reesei) for Effective Wastewater Treatment and Bio-Oil Production.

Biological wastewater treatment typically requires the use of bacteria for degradation of carbonaceous and nitrogenous compounds present in wastewater. The high lipid containing biomass can be used to extract oil and the contents can be termed as bio-oil (or biodiesel or myco-diesel after transesterification). The separate experiments were conducted on actual wastewater samples with 5% v/v inoculum of Mucor circinelloides MTCC1297 and Trichoderma reesei NCIM992 strains. The observed reductions in chemical oxygen demand (COD) were 88.72% and 86.75% in 96 hrs and the observed substrate based biomass yields were 0.21 mg VSS/mg COD and 0.22 mg VSS/mg COD for M. circinelloides reactor and for T. reesei reactor, respectively. The resulted bio-oil production from wastewater treatment by M. circinelloides and T. reesei reactors was 142.2 mg/L and 74.1 mg/L, whereas biomass containing bio-oil contents (%w/w) were 22.11% and 9.82%, respectively. In this experiment, the fungal wastewater treatment was also compared with conventional bacterial process with respect to specific growth rate, biomass production, and oil content. This study suggests that wastewater can be used as a potential feedstock for bio-oil production with the use of oleaginous fungal strains and which could be a possible route of waste to energy.