METTL3 governs thymocyte development and thymic involution by regulating ferroptosis.

Given its central role in immune aging, it is important to identify the regulators of thymic involution. While conventional programmed cell death has a fundamental role in thymocyte development, how cell death pathways contribute to thymic involution are unclear. In this study, we found that CD4+CD8+ double-positive (DP) thymocytes acquired the characteristics of senescence in aged mice undergoing thymic involution, while expression of the m6A methyltransferase-like protein 3 (METTL3), which is enriched in DP cells from young mice, decreased with aging. By conditionally deleting METTL3 in T cells, we revealed a critical role for METTL3 in DP cell survival and in restraining the features of aging in DP thymocytes by preventing ferroptosis signaling through glutathione peroxidase 4. Mechanistically, glutathione peroxidase 4 was maintained by METTL3 at the translational level, independently of its methyltransferase activity. Furthermore, we found that pharmacological inhibition of ferroptosis promoted DP cell survival and attenuated the features of aging in DP thymocytes. These findings uncover a role for METTL3-regulated ferroptosis in thymic involution and identify strategies to restore thymic function.

STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis by targeting HK2.

Evasion of antitumour immunity is a hallmark of cancer. STING, a putative innate immune signalling adaptor, has a pivotal role in mounting antitumour immunity by coordinating innate sensing and adaptive immune surveillance in myeloid cells. STING is markedly silenced in various human malignancies and acts as a cell-intrinsic tumour suppressor. How STING exerts intrinsic antitumour activity remains unclear. Here, we report that STING restricts aerobic glycolysis independent of its innate immune function. Mechanistically, STING targets hexokinase II (HK2) to block its hexokinase activity. As such, STING inhibits HK2 to restrict tumour aerobic glycolysis and promote antitumour immunity in vivo. In human colorectal carcinoma samples, lactate, which can be used as a surrogate for aerobic glycolysis, is negatively correlated with STING expression level and antitumour immunity. Taken together, this study reveals that STING functions as a cell-intrinsic metabolic checkpoint that restricts aerobic glycolysis to promote antitumour immunity. These findings have important implications for the development of STING-based therapeutic modalities to improve antitumour immunotherapy.

Nanosheets of two-dimensional photoluminescent lanthanide phosphonocarboxylate frameworks decorated with free carboxylic groups for latent fingerprint imaging.

The synthesis, structural characterization, exfoliation, and photophysical studies of two-dimensional (2-D) lanthanide phosphonates, named Ln(m-pbc); [Ln(m-Hpbc)(m-H2pbc)(H2O)] (Ln = Eu, Tb; m-pbc = 3-phosphonobenzoic acid) based on the phosphonocarboxylate ligand, are reported. These compounds are neutral polymeric 2D layered structures with pendent uncoordinated carboxylic groups between layers. The nanosheets were obtained by a top-down strategy involving sonication-assisted solution exfoliation and characterized by atomic force microscopy and transmission electron microscropy, showing lateral dimensions from nano- to micro-meter scales, and thicknesses down to several layers. The photoluminescence studies demonstrate that the m-pbc ligand acts as an efficient antenna toward Eu and Tb(III) ions. The emission intensities of dimetallic compounds are clearly enhanced after incorporation of Y(III) ions due to the dilution effect. Ln(m-pbc)s were then applied for labelling latent fingerprints. It is worth noting that the reaction between active carboxylic groups and fingerprint residues benefits the labelling, showing efficient imaging for fingerprints on all kinds of material surfaces.

trim-21 promotes proteasomal degradation of CED-1 for apoptotic cell clearance in C. elegans.

The phagocytic receptor CED-1 mediates apoptotic cell recognition by phagocytic cells, enabling cell corpse clearance in Caenorhabditis elegans. Whether appropriate levels of CED-1 are maintained for executing the engulfment function remains unknown. Here, we identified the C. elegans E3 ubiquitin ligase tripartite motif containing-21 (TRIM-21) as a component of the CED-1 pathway for apoptotic cell clearance. When the NPXY motif of CED-1 was bound to the adaptor protein CED-6 or the YXXL motif of CED-1 was phosphorylated by tyrosine kinase SRC-1 and subsequently bound to the adaptor protein NCK-1 containing the SH2 domain, TRIM-21 functioned in conjunction with UBC-21 to catalyze K48-linked poly-ubiquitination on CED-1, targeting it for proteasomal degradation. In the absence of TRIM-21, CED-1 accumulated post-translationally and drove cell corpse degradation defects, as evidenced by direct binding to VHA-10. These findings reveal a unique mechanism for the maintenance of appropriate levels of CED-1 to regulate apoptotic cell clearance.

Loss of Function of Scavenger Receptor SCAV-5 Protects C. elegans Against Pathogenic Bacteria.

Scavenger receptors play a critical role in innate immunity by acting as the pattern-recognition receptors. There are six class B scavenger receptors homologs in C. elegans. However, it remains unclear whether they are required for host defense against bacterial pathogens. Here, we show that, of the six SCAV proteins, only loss of function scav-5 protect C. elegans against pathogenic bacteria S. typhimurium SL1344 and P. aeruginosa PA14 by different mechanism. scav-5 mutants are resistant to S. typhimurium SL1344 due to dietary restriction. While scav-5 acts upstream of or in parallel to tir-1 in conserved PMK-1 p38 MAPK pathway to upregulate the innate immune response to defend worms against P. aeruginosa PA14. This is the first demonstration of a role for SCAV-5 in host defense against pathogenic bacteria. Our results provide an important basis for further elucidating the underlying molecular mechanism by which scav-5 regulates innate immune responses.

Multimetal lanthanide phosphonocarboxylate frameworks: structures, colour tuning and near-infrared emission.

A series of isostructural lanthanide phosphonocarboxylate frameworks {(H3O)3[Ln7(pbpdc)6(DMF)4(H2O)3]·4H2O}n (named LnPCF, Ln = Tb, Eu and Gd, H4pbpdc = 4'-phosphono-[1,1'-biphenyl]-3,5-dicarboxylic acid) were solvothermally synthesized and characterized by the single crystal X-ray diffraction technique. By combining lanthanide cations with a phosphonocarboxylate ligand, a heptametallic lanthanide phosphonate [Ln7(PO3)6(COO)12] core was obtained. This core exhibited as a rare highly 18-connected node and was linked by the 3-connected pbpdc4- ligand, forming a (3,18)-connected framework with a novel topology of {43}6{438·676·839}. This LnPCF structure is an ideal platform for accommodating various lanthanide ions. The TbPCF and EuPCF show efficient luminescence emission due to the "antenna effect" and incorporating Gd3+ into the TbPCF results in a drastic luminescence enhancement. Fine colour tuning between green and red can be easily achieved in bimetallic TbxGd1-xPCFs. More significantly, upon combining a few percent of Nd3+ and Gd3+ with Tb3+, the resulting trimetallic Tb0.4Gd0.5Nd0.1PCF shows dual emissions of both visible and near-infrared light.

SUMO modification in apoptosis.

Apoptosis and clearance of dead cells is highly evolutionarily conserved from nematode to humans, which is crucial to the growth and development of multicellular organism. Fail to remove apoptotic cells often lead to homeostasis imbalance, fatal autoimmune diseases, and neurodegenerative diseases. Small ubiquitin-related modifiers (SUMOs) modification is a post-translational modification of ubiquitin proteins mediated by the sentrin-specific proteases (SENPs) family. SUMO modification is widely involved in many cellular biological process, and abnormal SUMO modification is also closely related to many major human diseases. Recent researches have revealed that SUMO modification event occurs during apoptosis and clearance of apoptotic cells, and plays an important role in the regulation of apoptotic signaling pathways. This review summarizes some recent progress in the revelation of regulatory mechanisms of these pathways and provides some potential researching hotpots of the SUMO modification regulation to apoptosis.

Defective apoptotic cell clearance activates innate immune response to protect Caenorhabditis elegans against pathogenic bacteria.

Appropriate clearance of dead cells generated by apoptosis is critical to the development of multicellular organisms and tissue homeostasis. In mammals, the removal of apoptotic cell is mediated by polarized monocyte/macrophage populations of the innate immune system. The innate immune system is essential for anti-viral and anti-microbial defense. However, our current understanding of the relationship between apoptotic cell clearance and the innate immune response has remained rather limited. Here, we study how apoptotic cell clearance programs contribute to the innate immune response in C. elegans. We find apoptotic cell clearance mutant worms are more resistant to pathogenic bacteria of Pseudomonas aeruginosa PA14 and Salmonella typhimurium SL1344 due to significant upregulation of innate immune-dependent pathogen response genes. In addition, genetic epistasis analysis indicates that defects in apoptotic cell clearance can activate the innate immune response through PMK-1 p38 MAPK and MPK-1/ERK MAPK pathways in C. elegans. Taken together, our results provide evidence that insufficient clearance of apoptotic cell can protect Caenorhabditis elegans from bacterial infection through innate immune response activation.

[Expressions of TNF-alpha, IL-6, CRP, and MCP-1 in phlegm-damp constitution population detected by multiplexed Luminex assay].

OBJECTIVE: To study the expression changes of tumor necrosis factor-alpha (TNF-(alpha), interleukin-6 (IL-6), C-reactive protein (CRP), monocyte chemotactic protein 1 (MCP-1), and their correlation with obesity in 20 -50 years old population of phlegm-damp constitution (PDC) and of normal constitution (NC) using Luminex technique. METHODS: Totally 101 population were recruited from Health Examination Center of Puren Hospital from April to December 2011. Based on body mass index (BMI), the subjects were assigned to four groups, i.e., the obesity of PDC group (Group OBT, BMI > or = 24 kg/m2, 30 cases), the non-obesity of PDC group (Group NOBT, BMI < 24 kg/m2, 25 cases), the obesity of non-PDC group (Group OBNT, BMI > or = 24 kg/m2, 28 cases), the NC group (Group P, BMI < 24 kg/m2, 18 cases). The BMI and body fat percent (FAT%) were compared among the 4 groups. Serum levels of TNF-alpha, IL-6, CRP, and MCP-1 were measured with Luminex technique. RESULTS: BMI was significantly higher in Group OBT and Group OBNT than in Group NOBT and Group P (all P < 0.05). The FAT% was significantly higher in Group OBT and Group OBNT than in Group P (P < 0.01). The serum TNF-alpha level in Group OBT was higher than in Group P (P < 0.01). The serum CRP and MCP-1 levels were significantly higher in Group OBT, NOBT, and OBNT than in Group P (P < 0.05, P < 0.01). The score for PDC was positively correlated with TNF-alpha, IL-6, and MCP-1 levels (P < 0.05). CONCLUSIONS: Abnormal higher levels of inflammatory factors exist in 20 -50 years old population of PDC. Chronic inflammation exists in population of PDC and obesity people.