Highlights d Ablation of Gclc in Tregs causes autoimmunity and increases anti-tumor responses d Gclc-derived GSH is needed for the suppressive function of Tregs in vitro and in vivo d GSH in Tregs regulates serine concentrations and metabolism. which impact mTOR and FoxP3 d Serine-and glycine-deficient diet rescues mutant mice from lethal inflammation
Complex and hybrid N-glycans contain sugar residues that have been implicated in fertilization, compaction of the embryo, and implantation. Inactivation of the Mgat1 gene responsible for their synthesis is embryonic lethal, but homozygous mutant blastocysts are phenotypically normal due to the presence of maternal Mgat1 gene transcripts. To identify roles for complex and hybrid N-glycans in oogenesis and preimplantation development, the Mgat1 gene in oocytes was deleted by using a ZP3Cre recombinase transgene. All mutant oocytes had an altered zona pellucida (ZP) that was thinner than the control ZP, and they did not possess complex N-glycans but contained ZP1, ZP2, and ZP3 glycoproteins. Mutant eggs were fertilized, all embryos implanted, and heterozygotes developed to birth. However, mutant females had decreased fertility, yielded fewer eggs after stimulation with gonadotropins, and produced a reduced number of preimplantation embryos and less progeny than controls. About 25% of embryonic day 3.5 (E3.5) embryos derived from mutant eggs were severely retarded in development, even when they were heterozygous and expressed complex N-glycans. Thus, a proportion of Mgat1 ؊/؊ oocytes were developmentally compromised. Surprisingly, mutant eggs also gave rise to Mgat1 ؊/؊ embryos that developed normally, implanted, and progressed to E9.5. Therefore, complex or hybrid N-glycans are required at some stage of oogenesis for the generation of a developmentally competent oocyte, but fertilization, blastogenesis, and implantation may proceed in their absence.
Glycosylphosphatidylinositol (GPI)-anchored proteins are synthesized on membrane-bound ribosomes, translocated across the endoplasmic reticulum membrane, and GPI-anchored by GPI transamidase (GPIT). GPIT is a minimally heterotetrameric membrane protein complex composed of Gaa1, Gpi8, PIG-S and PIG-T. We describe structure-function analyses of Gaa1, the most hydrophobic of the GPIT subunits, with the aim of assigning a functional role to the different sequence domains of the protein. We generated epitope-tagged Gaa1 mutants and analyzed their membrane topology, subcellular distribution, complex-forming capability, and ability to restore GPIT activity in Gaa1-deficient cells. We show that (i) detergent-extracted, Gaa1-containing GPIT complexes sediment unexpectedly rapidly at ϳ17 S, (ii) Gaa1 is an endoplasmic reticulum-localized membrane glycoprotein with a cytoplasmically oriented N terminus and a lumenally oriented C terminus, (iii) elimination of C-terminal transmembrane segments allows Gaa1 to interact with other GPIT subunits but renders the resulting GPIT complex nonfunctional, (iv) interaction between Gaa1 and other GPIT subunits occurs via the large lumenal domain of Gaa1 located between the first and second transmembrane segments, and (v) the cytoplasmic N terminus of Gaa1 is not required for formation of a functional GPIT complex but may act as a membrane-sorting determinant directing Gaa1 and associated GPIT subunits to an endoplasmic reticulum membrane domain.
38 Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme into the tricarboxylic acid (TCA) cycle. Here we show that 39 PARK7/DJ-1, a key familial Parkinson's disease (PD) gene, is a pacemaker controlling PDH activity in CD4 regulatory 40 T cells (Tregs). DJ-1 bound to PDH-E1 beta (PDHB), inhibiting the phosphorylation of PDH-E1 alpha (PDHA), thus 41 promoting PDH activity and oxidative phosphorylation (OXPHOS). Dj-1 depletion impaired Treg proliferation and 42 cellularity maintenance in older mice, increasing the severity during the remission phase of experimental autoimmune 43 encephalomyelitis (EAE). The compromised proliferation and differentiation of Tregs in Dj-1 knockout mice were caused 44 via regulating PDH activity. These findings provide novel insight into the already complicated regulatory machinery of 45 the PDH complex and demonstrate that the DJ-1-PDHB axis represents a potent target to maintain Treg homeostasis, 46 which is dysregulated in many complex diseases. 47 48 9 Bonifati, V. et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset 789 parkinsonism. Science 299, 256-259, 792 11 van der Brug, M. P. et al. RNA binding activity of the recessive parkinsonism protein DJ-1 supports 793 involvement in multiple cellular pathways.
Regulatory T cells (Tregs) are critical for peripheral immune tolerance and homeostasis, and altered Treg behavior is involved in many pathologies, including autoimmunity and cancer. The expression of the transcription factor FoxP3 in Tregs is fundamental to maintaining their stability and immunosuppressive function. Recent studies have highlighted the crucial role that metabolic reprogramming plays in controlling Treg plasticity, stability, and function. In this review, we summarize how the availability and use of various nutrients and metabolites influence Treg metabolic pathways and activity. We also discuss how Treg‐intrinsic metabolic programs define and shape their differentiation, FoxP3 expression, and suppressive capacity. Lastly, we explore how manipulating the regulation of Treg metabolism might be exploited in different disease settings to achieve novel immunotherapies.
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