A milder form of NSRP1-associated neurodevelopmental disorder, caused by a missense variant in the nuclear localization signal.

Nuclear Speckle Splicing Regulator Protein 1 (NSRP1) is a splice factor found in nuclear speckles, which are small membrane-free organelles implicated in epigenetic regulation, chromatin organization, DNA repair, and RNA modification. Bi-allelic loss-of-function variants in NSRP1 have recently been identified in patients suffering from a severe neurodevelopmental disorder, presenting with neurodevelopmental delay, epilepsy, microcephaly, hypotonia, and spastic cerebral palsy. Described patients acquired neither independent walking nor speech and often showed anomalies on cerebral MRI.

Cell Type- and Age-Specific Expression of lncRNAs across Kidney Cell Types.

Key Points: We constructed a single-cell long noncoding RNA atlas of various tissues, including normal and aged kidneys. We identified age- and cell type–specific expression changes of long noncoding RNAs in kidney cells.

Background: Accumulated evidence demonstrates that long noncoding RNAs (lncRNAs) regulate cell differentiation and homeostasis, influencing kidney aging and disease.

Discovery of antiviral SARS-CoV-2 main protease inhibitors by structure-guided hit-to-lead optimization of carmofur.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M) has been targeted for the development of anti-SARS-CoV-2 agents against COVID-19 infection because M processes essential viral polyproteins and plays a key role in SARS-CoV-2 replication. In this study, we report the development of novel SARS-CoV-2 M inhibitors derived from carmofur, a previously identified compound that has shown moderate potency as a covalent inhibitor of SARS-CoV-2 M. To employ a structure-guided drug design strategy, a putative intact binding mode of carmofur at catalytic active site of M was initially predicted by docking simulation.

The Immunosuppressive Potential of Cholesterol Sulfate Through T Cell Microvilli Disruption.

Cholesterol (CL) is required for various biomolecular production processes, including those of cell membrane components. Therefore, to meet these needs, CL is converted into various derivatives. Among these derivatives is cholesterol sulfate (CS), a naturally produced CL derivative by the sulfotransferase family 2B1 (SULT2B1), which is widely present in human plasma.

Trogocytic molting of T cell microvilli upregulates T cell receptor surface expression and promotes clonal expansion.

Although T cell activation is known to involve the internalization of the T cell antigen receptor (TCR), much less is known regarding the release of TCRs following T cell interaction with cognate antigen-presenting cells. In this study, we examine the physiological mechanisms underlying TCR release following T cell activation. We show that T cell activation results in the shedding of TCRs in T cell microvilli, which involves a combined process of trogocytosis and enzymatic vesiculation, leading to the loss of membrane TCRs and microvilli-associated proteins and lipids.

T Cell Immunological Synaptosomes: Definition and Isolation.

In addition to microvilli's role as structural scaffold for TCR clustering, we recently discovered a novel function as message senders. We found that microvilli are separated from the T cell body shortly upon TCR stimulation and vesiculated to form T cell microvilli particles (TMPs), a new type of membrane vesicles. TMPs and synaptic ectosomes, which bud from the synaptic cleft, constitute "T cell immunological synaptosomes (TISs)" and act as conveyors of T cell messages or traits to cognate antigen-presenting cells.

ST3GAL1 and βII-spectrin pathways control CAR T cell migration to target tumors.

Adoptive transfer of genetically engineered chimeric antigen receptor (CAR) T cells is becoming a promising treatment option for hematological malignancies. However, T cell immunotherapies have mostly failed in individuals with solid tumors. Here, with a CRISPR-Cas9 pooled library, we performed an in vivo targeted loss-of-function screen and identified ST3 β-galactoside α-2,3-sialyltransferase 1 (ST3GAL1) as a negative regulator of the cancer-specific migration of CAR T cells.

T Cell Microvilli: Finger-Shaped External Structures Linked to the Fate of T Cells.

Microvilli are outer membrane organelles that contain cross-linked filamentous actin. Unlike well-characterized epithelial microvilli, T-cell microvilli are dynamic similar to those of filopodia, which grow and shrink intermittently via the alternate actin-assembly and -disassembly. T-cell microvilli are specialized for sensing Ags on the surface of Ag-presenting cells (APCs).

NSrp70 is a lymphocyte-essential splicing factor that controls thymocyte development.

Alternative pre-mRNA splicing is a critical step to generate multiple transcripts, thereby dramatically enlarging the proteomic diversity. Thus, a common feature of most alternative splicing factor knockout models is lethality. However, little is known about lineage-specific alternative splicing regulators in a physiological setting.

Transgelin-2: A Double-Edged Sword in Immunity and Cancer Metastasis.

Transgelin-2, a small actin-binding protein, is the only transgelin family member expressed in immune cells. In T and B lymphocytes, transgelin-2 is constitutively expressed, but in antigen-presenting cells, it is significantly upregulated upon lipopolysaccharide stimulation. Transgelin-2 acts as a molecular staple to stabilize the actin cytoskeleton, and it competes with cofilin to bind filamentous (F)-actin.

Licoricidin Abrogates T-Cell Activation by Modulating PTPN1 Activity and Attenuates Atopic Dermatitis In Vivo.

Licoricidin, the fifth-highest fraction among the isolated 48 molecules from Glycyrrhiza uralensis extracts, has been known as an anti-inflammatory bioactive molecule; however, few studies have shown its inhibitory effect on T-cell activation and atopic dermatitis (AD). This study examined the therapeutic potential of licoricidin in AD by modulating T-cell activation with molecular mechanisms. Licoricidin attenuated the expression of IL-2 mRNA in stimulated T cells without cytotoxicity.

Cell-permeable transgelin-2 as a potent therapeutic for dendritic cell-based cancer immunotherapy.

Background: Transgelin-2 is a 22 kDa actin-binding protein that has been proposed to act as an oncogenic factor, capable of contributing to tumorigenesis in a wide range of human malignancies. However, little is known whether this tiny protein also plays an important role in immunity, thereby keeping body from the cancer development and metastasis. Here, we investigated the functions of transgelin-2 in dendritic cell (DC) immunity.

Potentiating the Antitumor Activity of Cytotoxic T Cells the Transmembrane Domain of IGSF4 That Increases TCR Avidity.

A robust T-cell response is an important component of sustained antitumor immunity. In this respect, the avidity of TCR in the antigen-targeting of tumors is crucial for the quality of the T-cell response. This study reports that the transmembrane (TM) domain of immunoglobulin superfamily member 4 (IGSF4) binds to the TM of the CD3 ζ-chain through an interaction between His177 and Asp36, which results in IGSF4-CD3 ζ dimers.

Structural and Biochemical Characterization of EFhd1/Swiprosin-2, an Actin-Binding Protein in Mitochondria.

Ca regulates several cellular functions, including signaling events, energy production, and cell survival. These cellular processes are mediated by Ca-binding proteins, such as EF-hand superfamily proteins. Among the EF-hand superfamily proteins, allograft inflammatory factor-1 (AIF-1) and swiprosin-1/EF-hand domain-containing protein 2 (EFhd2) are cytosolic actin-binding proteins.

Structural Characteristics, Binding Partners and Related Diseases of the Calponin Homology (CH) Domain.

The calponin homology (CH) domain is one of the most common modules in various actin-binding proteins and is characterized by an α-helical fold. The CH domain plays important regulatory roles in both cytoskeletal dynamics and signaling. The CH domain is required for stability and organization of the actin cytoskeleton, calcium mobilization and activation of downstream pathways.

T Cell Microvilli: Sensors or Senders?

Communication between cells is essential for multicellular life. During cognate immune interactions, T cells communicate with antigen-presenting cells (APC) via direct cell-cell contact or the release of molecules and vesicles containing T cell messages. A wide variety of mechanisms have been reported and among them a process called "trogocytosis" has traditionally been thought to be the fastest way to directly transfer membrane portions containing intact proteins from one cell to another; however, the mechanism is unverified.

Ets1 suppresses atopic dermatitis by suppressing pathogenic T cell responses.

Atopic dermatitis (AD) is a complex inflammatory skin disease mediated by immune cells of both adaptive and innate types. Among them, CD4+ Th cells are one of major players of AD pathogenesis. Although the pathogenic role of Th2 cells has been well characterized, Th17/Th22 cells are also implicated in the pathogenesis of AD.

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1.

Correct temporal and spatial control of actin dynamics is essential for the cytotoxic T cell effector function against tumor cells. However, little is known whether actin engineering in tumor-targeted T cells can enhance their antitumor responses, thereby potentiating the adoptive T cell therapy. Here, we report that TAGLN2, a 22-KDa actin-stabilizing protein which is physically associated with lymphocyte function-associated antigen-1 (LFA-1), potentiates the CD8 T cells to kill the intercellular adhesion molecule-1 (ICAM-1)-positive/OVA-presenting E0771 cells, but not ICAM-1-negative OVA-B16F10 cells, suggesting an 'inside-out' activation of LFA-1, which causes more efficient immunological synapse formation between T cells and tumor cells.

Conserved Noncoding Sequences Boost ADR1 and SP1 Regulated Human Swiprosin-1 Promoter Activity.

Swiprosin-1 is expressed in various types of cells or tissues of different species. To investigate the mechanisms underlying Swiprosin-1 expression pattern, we analyzed the promoter activity of 2-kilobase genomic sequences located at 5' flanking region of the Swiprosin-1 gene. The -2000/+41 bp of 5' flanking untranslated promoter region of Swiprosin-1 gene was constitutively transactivated without significant effect of PMA, A23187, or PMA/A23187 stimulation in Jurkat T cells.

Cell surface polysaccharides of induce the generation of Foxp3 regulatory T cells.

Dysregulation of intestinal microflora is linked to inflammatory disorders associated with compromised immunosuppressive functions of Foxp3 T regulatory (T) cells. Although mucosa-associated commensal microbiota has been implicated in T generation, molecular identities of the "effector" components controlling this process remain largely unknown. Here, we have defined as a potent inducer of Foxp3 T cells with diverse T cell receptor specificity to dietary antigens, commensal bacteria, and itself.

T cell microvilli constitute immunological synaptosomes that carry messages to antigen-presenting cells.

Microvilli on T cells have been proposed to survey surfaces of antigen-presenting cells (APC) or facilitate adhesion under flow; however, whether they serve essential functions during T cell activation remains unclear. Here we show that antigen-specific T cells deposit membrane particles derived from microvilli onto the surface of cognate antigen-bearing APCs. Microvilli carry T cell receptors (TCR) at all stages of T cell activation and are released as large TCR-enriched, T cell microvilli particles (TMP) in a process of trogocytosis.

Real-Time Monitoring of Cancer Cells in Live Mouse Bone Marrow.

Disseminated tumor cells in the bone marrow environment are the main cause of systemic metastasis after curative treatment for major solid tumors. However, the detailed biological processes of tumor biology in bone marrow have not been well defined in a real-time manner, because of a lack of a proper experimental model thereof. In this study, we established intravital imaging models of the bone marrow environment to enable real-time observation of cancer cells in the bone marrow.