Inhibition of SHP-1 activity by PKC-θ regulates NK cell activation threshold and cytotoxicity.

Natural killer (NK) cells play a crucial role in immunity, killing virally infected and cancerous cells. The balance of signals initiated upon engagement of activating and inhibitory NK receptors with cognate ligands determines killing or tolerance. Nevertheless, the molecular mechanisms regulating rapid NK cell discrimination between healthy and malignant cells in a heterogeneous tissue environment are incompletely understood.

High-Throughput Imaging of CRISPR- and Recombinant Adeno-Associated Virus-Induced DNA Damage Response in Human Hematopoietic Stem and Progenitor Cells.

CRISPR-Cas technology has revolutionized gene editing, but concerns remain due to its propensity for off-target interactions. This, combined with genotoxicity related to both CRISPR-Cas9-induced double-strand breaks and transgene delivery, poses a significant liability for clinical genome-editing applications. Current best practice is to optimize genome-editing parameters in preclinical studies.

The Ebola-Glycoprotein Modulates the Function of Natural Killer Cells.

The Ebola virus (EBOV) uses evasion mechanisms that directly interfere with host T-cell antiviral responses. By steric shielding of human leukocyte antigen class-1, the Ebola glycoprotein (GP) blocks interaction with T-cell receptors (TCRs), thus rendering T cells unable to attack virus-infected cells. It is likely that this mechanism could promote increased natural killer (NK) cell activity against GP-expressing cells by preventing the engagement of NK inhibitory receptors; however, we found that primary human NK cells were less reactive to GP-expressing HEK293T cells.

Actin retrograde flow controls natural killer cell response by regulating the conformation state of SHP-1.

Natural killer (NK) cells are a powerful weapon against viral infections and tumor growth. Although the actin-myosin (actomyosin) cytoskeleton is crucial for a variety of cellular processes, the role of mechanotransduction, the conversion of actomyosin mechanical forces into signaling cascades, was never explored in NK cells. Here, we demonstrate that actomyosin retrograde flow (ARF) controls the immune response of primary human NK cells through a novel interaction between β-actin and the SH2-domain-containing protein tyrosine phosphatase-1 (SHP-1), converting its conformation state, and thereby regulating NK cell cytotoxicity.

Robo Ig4 Is a Dimerization Domain.

Robo receptors play pivotal roles in axonal guidance as well as in neurogenesis, angiogenesis, cell migration, and cancer progression and invasiveness. They are considered to be attractive drug targets for the treatment of cancer, ocular neovascular disorders, chronic kidney diseases, and more. Despite their great importance, the mechanisms by which Robo receptors switch from their "off" to "on" states remain obscure.

Cbl ubiquitin ligases mediate the inhibition of natural killer cell activity.

Natural killer (NK) cells are essential for killing transformed and virally infected cells. To prevent auto-reactivity, NK cell activation is inhibited by inhibitory receptors that activate the tyrosine phosphatase SHP-1, which dephosphorylates signaling molecules crucial for NK cell activation. Initially, only a single SHP-1 substrate was identified in NK cells, the GEF VAV1.

Dephosphorylation of the adaptor LAT and phospholipase C-γ by SHP-1 inhibits natural killer cell cytotoxicity.

Natural killer (NK) cells discriminate between healthy cells and virally infected or transformed self-cells by tuning activating and inhibitory signals received through cell surface receptors. Inhibitory receptors inhibit NK cell function by recruiting and activating the tyrosine phosphatase Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-1 (SHP-1) to the plasma membrane. However, to date, the guanine nucleotide exchange factor VAV1 is the only direct SHP-1 substrate identified in NK cells.

Ubiquitylation-dependent downregulation of Nck regulates its functional activity.

The Nck adapter protein is involved in key cellular functions, such as actin polymerization and reorganization, serving as a molecular bridge between the surface complex essential for foreign antigen recognition, the T-cell antigen receptor (TCR), and the actin machinery. However, the mechanisms regulating Nck expression and functions are unknown. In this study, we revealed Nck negative regulation and demonstrated that Nck is ubiquitylated following cellular activation.

WIP: more than a WASp-interacting protein.

WIP plays an important role in the remodeling of the actin cytoskeleton, which controls cellular activation, proliferation, and function. WIP regulates actin polymerization by linking the actin machinery to signaling cascades. WIP binding to WASp and to its homolog, N-WASp, which are central activators of the actin-nucleating complex Arp2/3, regulates their cellular distribution, function, and stability.

Triple-color FRET analysis reveals conformational changes in the WIP-WASp actin-regulating complex.

Wiskott-Aldrich syndrome protein (WASp) is a key regulator of the actin cytoskeletal machinery. Binding of WASp-interacting protein (WIP) to WASp modulates WASp activity and protects it from degradation. Formation of the WIP-WASp complex is crucial for the adaptive immune response.

Wiskott-Aldrich syndrome protein--dynamic regulation of actin homeostasis: from activation through function and signal termination in T lymphocytes.

The actin cytoskeleton network forms a key link between T-cell antigen receptor (TCR) stimulation and T-cell effector functions, providing a structural basis for T-cell morphological changes and signal transduction. Accumulating evidence positions the Wiskott-Aldrich syndrome protein (WASp), a scaffolding protein that promotes actin polymerization, at the center of actin cytoskeleton-dependent T-cell function. During the past decade, we and others have utilized multidisciplinary technologies, including live-cell imaging, biochemical, and biophysical analyses, to gain insight into the mechanisms by which WASp and other cytoskeletal proteins control actin homeostasis.

WIP remodeling actin behind the scenes: how WIP reshapes immune and other functions.

Actin polymerization is a fundamental cellular process regulating immune cell functions and the immune response. The Wiskott-Aldrich syndrome protein (WASp) is an actin nucleation promoting factor, which is exclusively expressed in hematopoietic cells, where it plays a key regulatory role in cytoskeletal dynamics. WASp interacting protein (WIP) was first discovered as the binding partner of WASp, through the use of the yeast two hybrid system.