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LUBAC is a ubiquitin ligase complex of HOIL-1, HOIP and SHARPIN important for signal transduction of a range of stimuli. Here the authors define the function of all three LUBAC components in T cell development and homeostasis.

S63845 specifically inhibits MCL1 and induces tumour cell death in vitro and in vivo in diverse cancer-derived cell lines with an acceptable safety margin.

The comprehensive bioanalysis of proteins usually requires multi-step surface and mobile phase measurements. Here, the authors use chips functionalized with dynamically actuated nanolevers—DNA strands that can be switched in an electric field—to obtain motional dynamic measurements of proteins on a chip.

Mcl-1 is an important survival factor for several hematopoietic lineages including B and T lymphocytes, but its role in the Natural Killer (NK) cells has not been previously tested. Here, the authors report that deletion of Mcl-1 in the NK cell lineage leads to the loss of NK cells from all tissues.

Platelet production has been suggested to occur by apoptosis of megakaryocytes, but mitochondrially mediated apoptosis is known to be dispensable. Here, the authors show that death receptor-mediated apoptosis in mouse megakaryocytes is also not required for platelet biogenesis.

Trapped ion mobility (TIMS)-mass spectrometry with parallel accumulation-serial fragmentation (PASEF) facilitates high-sensitivity proteomics experiments. Here, the authors expand TIMS and PASEF to small molecules and demonstrate fast and comprehensive lipidomics of low biological sample amounts.

Successful passage through several developmental checkpoints determines whether thymocytes survive, proliferate or differentiate. New data show that Wnt-frizzled–induced activation of TCF-1 or Lef-1, via their coactivator β-catenin, is critical during TCRB and TCRA gene rearrangement in thymocytes.

Adjuvants and inflammation inhibit TCR ligation-induced apoptosis of T cells. Bcl-3 may enhance the increased T cell survival by positive regulation of NF-κB transcription factors.

Cells experiencing extended mitotic arrest often undergo cell death as a result of steadily declining levels of the apoptotic inhibitor MCL1, but the mechanism controlling this process is poorly understood. Here, Haschka et al.show that the BH3-only protein NOXA promotes the degradation of MCL1, enabling BIM-dependent cell death.

BCL-2 family proteins have either pro- or anti-apoptotic activities that are crucial for the regulation of apoptosis, tumorigenesis and cellular responses to anti-cancer therapy. Recent advances suggest that interactions between BCL-2 family proteins affect their localization and conformation and regulate their bioactivity.

Tom Karlsen and colleagues report a genome-wide association study for primary sclerosing cholangitis, a chronic bile duct disease. They identify susceptibility loci at MST1 and near BCL2L11.

TNF mediated inflammation is critical in autoimmune mediated pathology, however many patients are refractory to current anti-TNF therapeutics. Here the authors show induction of several death ligands, in addition to TNF is sufficient to cause fatal dermatitis in a LUBAC deficient murine model of disease.

The signals controlling T_reg cell homeostasis and survival are still being determined. Liston and colleagues demonstrate that peripheral T_reg cells depend critically on IL-2 and the survival factor Mcl-1 but not on Bcl-2.

B cell development requires interleukin 7 signals that activate the transcription factor STAT5. Busslinger and colleagues report that STAT5 has a permissive rather than instructive role in pro-B cell survival and immunoglobulin recombination.

Visvader and colleagues report that in the mouse mammary gland, EGF and mTOR signalling induce expression of the anti-apoptotic Bcl2 family member Mcl-1 and show that this is required for the survival of milk-producing mammary epithelial cells.

Immune surveillance has been proposed to eliminate transformed cells and thereby limit tumor formation. Axel Kallies and colleagues now report that spontaneous B cell lymphoma development in Blimp1-deficient or Bcl6-overexpressing mice is accelerated by T cell deficiency and identify the Fas-Fas ligand pathway as a crucial mediator of T cell control of lymphoma growth.

diaPASEF makes use of the correlation between the ion mobility and the m/z of peptides to trap and release precursor ions in a TIMS-TOF mass spectrometer for an almost complete sampling of the precursor ion beam with data-independent acquisition.

Research on the BCL-2-regulated apoptotic pathway has led to the development of small molecules called BH3-mimetics that bind to pro-survival BCL-2 proteins to induce apoptosis of malignant cells. This Timeline article describes the history of research on the BCL-2 family of proteins and their roles in cancer.

Interactions on the mitochondrial outer membrane between members of the three subgroups of the BCL-2 protein family set the apoptotic threshold. Recent structural insights into the molecular mechanisms of this commitment to apoptosis are guiding the development of new therapeutics for cancer, and potentially also autoimmune and infectious diseases.

Fas ligand (FasL) and its receptor Fas are critical for the shutdown of chronic immune responses and prevention of autoimmunity. FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding, but it is unclear what the respective roles of these secreted and membrane-bound forms are. Gene-targeted mice that selectively lack either secreted FasL or membrane-bound FasL are now generated, shedding light on this problem.

Soil microbial activity is accelerated by warming and does not acclimate over periods of at least 50 years. Resulting soil carbon loss is nevertheless temporary because substrate depletion reduces microbial biomass and constrains the influence of microbes over the ecosystem.

Selective inhibitors of KAT6A and KAT6B inhibit MYST-catalysed histone acetylation, induce cell cycle exit and cellular senescence without causing DNA damage, and arrest lymphoma progression in mouse models.

The HOIL-1 component of the LUBAC ubiquitin ligase complex is required for LUBAC activity, which prevents lethality during embryogenesis by preventing aberrant TNFR1-mediated endothelial cell death and RIPK1-mediated defects in haematopoiesis.

Colonizing enteric bacteria are shown to inhibit the antimicrobial process of host cell apoptosis through the action of NleB1, a type III secretion system effector with N-acetylglucosamine transferase activity, which can bind and modify eukaryotic death-___domain-containing proteins.

Inhibition of BCL-XL eliminates Legionella infection, suggesting that host-directed BH3-mimetic therapy may be effective against intracellular pathogens that inhibit host cell protein synthesis.

In the absence of RIPK1, ZBP1 engages RIPK3 in a RHIM-dependent manner and acts as a critical activator of RIPK3/MLKL-dependent necroptosis.

BH3-mimetic drugs have been designed to directly induce apoptosis in cancer cells by targeting prosurvival BCL-2 family proteins. This Review discusses their continued development and the challenges arising from their implementation in the clinic, such as resistance or on-target toxic effects, and the approaches that could be harnessed to overcome these obstacles.

Dispensable, infected or neoplastic cells are removed by programmed cell death, including pathways for apoptosis, necroptosis and pyroptosis. Owing to differences in their mechanisms and physiological outcomes, these cell death pathways have traditionally been viewed as separate entities, but it has become clear that they are mechanistically and functionally connected.