SIRT7 remodels the cytoskeleton RAC1 to enhance host resistance to .

Phagocytosis of () followed by its integration into the matured lysosome is critical in the host defense against tuberculosis. How escapes this immune attack remains elusive. In this study, we unveiled a novel regulatory mechanism by which SIRT7 regulates cytoskeletal remodeling by modulating RAC1 activation.

Increased peritoneal B1-like cells during acute phase of human septic peritonitis.

Sepsis is a life-threatening condition caused by dysregulated host responses to infection. Myeloid cell accumulation and lymphocyte decline are widely recognized phenomena in septic patients. However, the fate of specific immune cells remains unclear.

Role of Rad18 in B cell activation and lymphomagenesis.

Maintenance of genome integrity is instrumental in preventing cancer. In addition to DNA repair pathways that prevent damage to DNA, damage tolerance pathways allow for the survival of cells that encounter DNA damage during replication. The Rad6/18 pathway is instrumental in this process, mediating damage bypass by ubiquitination of proliferating cell nuclear antigen.

Sepsis induces non-classic innate immune memory in granulocytes.

Secondary infection in patients with sepsis triggers a new wave of inflammatory response, which aggravates organ injury and increases mortality. Trained immunity boosts a potent and nonspecific response to the secondary challenge and has been considered beneficial for the host. Here, using a murine model of polymicrobial infection, we find that the primary infection reprograms granulocytes to boost enhanced inflammatory responses to the secondary infection, including the excessive production of inflammatory cytokines, respiratory burst, and augmented phagocytosis capacity.

RAGE is a critical factor of sex-based differences in age-induced kidney damage.

Advanced glycation end products (AGEs) are a heterogeneous group of molecules with potential pathophysiological effects on the kidneys. Fibrosis together with the accumulation of AGEs has been investigated for its contribution to age-related decline in renal function. AGEs mediate their effects in large parts through their interactions with the receptor for AGEs (RAGE).

Lessons from Using Genetically Engineered Mouse Models of MYC-Induced Lymphoma.

Oncogenic overexpression of MYC leads to the fatal deregulation of signaling pathways, cellular metabolism, and cell growth. rearrangements are found frequently among non-Hodgkin B-cell lymphomas enforcing MYC overexpression. Genetically engineered mouse models (GEMMs) were developed to understand MYC-induced B-cell lymphomagenesis.

Analyzing Lymphoma Development and Progression Using HDACi in Mouse Models.

Besides the physiological role of histone deacetalylases in maintaining normal cellular integrity, the acetylation landscape is changed in cancer cells, which has been implicated as a potential target in cancer therapy. The overexpression of certain HDACs correlates with specific cancer types. Therefore, the development of specific HDAC inhibitors may extend the therapeutic strategy for cancer therapy.

Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition.

Overexpression of MYC is a genuine cancer driver in lymphomas and related to poor prognosis. However, therapeutic targeting of the transcription factor MYC remains challenging. Here, we show that inhibition of the histone deacetylase 6 (HDAC6) using the HDAC6 inhibitor Marbostat-100 (M-100) reduces oncogenic MYC levels and prevents lymphomagenesis in a mouse model of MYC-induced aggressive B-cell lymphoma.

PI(18:1/18:1) is a SCD1-derived lipokine that limits stress signaling.

Cytotoxic stress activates stress-activated kinases, initiates adaptive mechanisms, including the unfolded protein response (UPR) and autophagy, and induces programmed cell death. Fatty acid unsaturation, controlled by stearoyl-CoA desaturase (SCD)1, prevents cytotoxic stress but the mechanisms are diffuse. Here, we show that 1,2-dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol) [PI(18:1/18:1)] is a SCD1-derived signaling lipid, which inhibits p38 mitogen-activated protein kinase activation, counteracts UPR, endoplasmic reticulum-associated protein degradation, and apoptosis, regulates autophagy, and maintains cell morphology and proliferation.

Myc-Interacting Zinc Finger Protein 1 (Miz-1) Is Essential to Maintain Homeostasis and Immunocompetence of the B Cell Lineage.

Aging of the immune system is described as a progressive loss of the ability to respond to immunologic stimuli and is commonly referred to as immunosenescence. B cell immunosenescence is characterized by a decreased differentiation rate in the bone marrow and accumulation of antigen-experienced and age-associated B cells in secondary lymphoid organs (SLOs). A specific deletion of the POZ-domain of the transcription factor Miz-1 in pro-B cells, which is known to be involved in bone marrow hematopoiesis, leads to premature aging of the B cell lineage.

Endoplasmic reticulum stress and the unfolded protein response in skeletal muscle of subjects suffering from peritoneal sepsis.

We provide a descriptive characterization of the unfolded protein response (UPR) in skeletal muscle of human patients with peritoneal sepsis and a sepsis model of C57BL/6J mice. Patients undergoing open surgery were included in a cross-sectional study and blood and skeletal muscle samples were taken. Key markers of the UPR and cluster of differentiation 68 (CD68) as surrogate of inflammatory injury were evaluated by real-time PCR and histochemical staining.

Context-dependent regulation of immunoglobulin mutagenesis by p53.

p53 plays a major role in genome maintenance. In addition to multiple p53 functions in the control of DNA repair, a regulation of DNA damage bypass via translesion synthesis has been implied in vitro. Somatic hypermutation of immunoglobulin genes for affinity maturation of antibody responses is based on aberrant translesion polymerase action and must be subject to stringent control to prevent genetic alterations and lymphomagenesis.

Dichotomous Impact of Myc on rRNA Gene Activation and Silencing in B Cell Lymphomagenesis.

A major transcriptional output of cells is ribosomal RNA (rRNA), synthesized by RNA polymerase I (Pol I) from multicopy rRNA genes (rDNA). Constitutive silencing of an rDNA fraction by promoter CpG methylation contributes to the stabilization of these otherwise highly active loci. In cancers driven by the oncoprotein Myc, excessive Myc directly stimulates rDNA transcription.

Deletion of the Miz-1 POZ Domain Increases Efficacy of Cytarabine Treatment in T- and B-ALL/Lymphoma Mouse Models.

Acute lymphoblastic leukemia (ALL) is an aggressive blood cancer that mainly affects children. Relapse rates are high and toxic chemotherapies that block DNA replication and induce DNA damage lead to health problems later in life, underlining the need for improved therapies. MYC is a transcription factor that is hyperactive in a large proportion of cancers including leukemia but is difficult to target in therapy.

A mouse model for SPG48 reveals a block of autophagic flux upon disruption of adaptor protein complex five.

Hereditary spastic paraplegia is a spastic gait disorder that arises from degeneration of corticospinal axons. The subtype SPG48 is associated with mutations in the zeta subunit of the adaptor protein complex five (AP5). AP5 function and the pathophysiology of SPG48 are only poorly understood.

Epigenetic Erosion in Adult Stem Cells: Drivers and Passengers of Aging.

In complex organisms, stem cells are key for tissue maintenance and regeneration. Adult stem cells replenish continuously dividing tissues of the epithelial and connective types, whereas in non-growing muscle and nervous tissues, they are mainly activated upon injury or stress. In addition to replacing deteriorated cells, adult stem cells have to prevent their exhaustion by self-renewal.

Tuberous sclerosis complex is required for tumor maintenance in MYC-driven Burkitt's lymphoma.

The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient-sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC-driven cancer.

Effects of HDACi on Immunological Functions.

Histone deacetylase inhibitors (HDACi) are used as therapeutics for several B cell-derived malignancies. Furthermore, they have been shown to modulate the response of the immune system, like the B cell function. HDACi treatment affects differentiation, proliferation, and survival of B cells.

Sepsis-Induced Thymic Atrophy Is Associated with Defects in Early Lymphopoiesis.

Impaired T lymphopoiesis is associated with immunosuppression of the adaptive immune response and plays a role in the morbidity and mortality of patients and animal models of sepsis. Although previous studies examined several intrathymic mechanisms that negatively affect T lymphopoiesis, the extrathymic mechanisms remain poorly understood. Here, we report a dramatic decrease in the percentage of early T lineage progenitors (ETPs) in three models of sepsis in mice (cecal ligation and puncture, lipopolysaccharide continuous injection, and poly I:C continuous injection).

Myofibroblasts have an impact on expression, dimerization and signaling of different ErbB receptors in OSCC cells.

Introduction: Receptors of the ErbB family belong to the key players in cancer development and are targets of several therapeutic approaches. Their functional dependency on the tumor microenvironment, especially on CAFs is albeit still poorly understood. Our objective was to investigate the impact of CAF secretome on ErbB receptor expression and signaling behavior in OSCC.

Genetic and Epigenetic Mechanisms That Maintain Hematopoietic Stem Cell Function.

All hematopoiesis cells develop from multipotent progenitor cells. Hematopoietic stem cells (HSC) have the ability to develop into all blood lineages but also maintain their stemness. Different molecular mechanisms have been identified that are crucial for regulating quiescence and self-renewal to maintain the stem cell pool and for inducing proliferation and lineage differentiation.

Miz-1 regulates translation of Trp53 via ribosomal protein L22 in cells undergoing V(D)J recombination.

To be effective, the adaptive immune response requires a large repertoire of antigen receptors, which are generated through V(D)J recombination in lymphoid precursors. These precursors must be protected from DNA damage-induced cell death, however, because V(D)J recombination generates double-strand breaks and may activate p53. Here we show that the BTB/POZ domain protein Miz-1 restricts p53-dependent induction of apoptosis in both pro-B and DN3a pre-T cells that actively rearrange antigen receptor genes.

The transcription factor Miz-1 is required for embryonic and stress-induced erythropoiesis but dispensable for adult erythropoiesis.

Myc-interacting zinc finger protein 1 (Miz-1) is a BTB/POZ domain transcription factor that regulates complex processes such as proliferation and apoptosis. Constitutively Miz-1-deficient animals arrest embryonic development at E14.5 due to severe anemia and fetal liver cells lacking Miz-1 show a high cell death rate and a significant reduction of mature Ter119(+)ckit(-) or Ter119(+)CD71(-/low) cells.

Arginine residues within the DNA binding domain of STAT3 promote intracellular shuttling and phosphorylation of STAT3.

Acetylation-dependent inactivation of STAT1 can be mimicked by the exchange of its lysine residues K410 and K413 to glutamine residues. STAT3 harbors non-acetylatable arginine moieties at the corresponding sites R414 and R417. It is unclear whether the mutation of these sites to glutamine residues antagonizes STAT3 activation.