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1.
Dev Cell ; 47(5): 592-607.e6, 2018 12 03.
Article in English | MEDLINE | ID: mdl-30513302

ABSTRACT

Regulatory T cells (Treg) are necessary to maintain immunological tolerance and are key players in the control of autoimmune disease susceptibility. Expression of the transcription factor FOXP3 is essential for differentiation of Treg cells and indispensable for their suppressive function. However, there is still a lack of knowledge about the mechanisms underlying its regulation. Here, we demonstrate that pro-autophagy protein AMBRA1 is also a key modulator of T cells, regulating the complex network that leads to human Treg differentiation and maintenance. Indeed, through its ability to interact with the phosphatase PP2A, AMBRA1 promotes the stability of the transcriptional activator FOXO3, which, in turn, triggers FOXP3 transcription. Furthermore, we found that AMBRA1 plays a significant role in vivo by regulating Treg cell induction in mouse models of both tumor growth and multiple sclerosis, thus highlighting the role of AMBRA1 in the control of immune homeostasis.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Cell Differentiation , T-Lymphocytes/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cells, Cultured , Forkhead Box Protein O3/genetics , Forkhead Box Protein O3/metabolism , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , HeLa Cells , Homeostasis , Humans , Jurkat Cells , Mice , Mice, Inbred C57BL , Multiple Sclerosis/metabolism , Protein Phosphatase 2/metabolism , T-Lymphocytes/cytology
2.
Mol Microbiol ; 79(2): 342-58, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21219456

ABSTRACT

Oxidation of methionine to methionine sulphoxide (MetSO) may lead to loss of molecular integrity and function. This oxidation can be 'repaired' by methionine sulphoxide reductases (MSRs), which reduce MetSO back to methionine. Two structurally unrelated classes of MSRs, MSRA and MSRB, show stereoselectivity towards the S and the R enantiomer of the sulphoxide respectively. Interestingly, these enzymes were even maintained throughout evolution in anaerobic organisms. Here, the activity and the nuclear magnetic resonance (NMR) structure of MTH711, a zinc containing MSRB from the thermophilic, methanogenic archaebacterium Methanothermobacter thermoautotrophicus, are described. The structure appears more rigid as compared with similar MSRBs from aerobic and mesophilic organisms. No significant structural differences between the oxidized and the reduced MTH711 state can be deduced from our NMR data. A stable sulphenic acid is formed at the catalytic Cys residue upon oxidation of the enzyme with MetSO. The two non-zinc-binding cysteines outside the catalytic centre are not necessary for activity of MTH711 and are not situated close enough to the active-site cysteine to serve in regenerating the active centre via the formation of an intramolecular disulphide bond. These findings imply a reaction cycle that differs from that observed for other MSRBs.


Subject(s)
Archaeal Proteins/chemistry , Archaeal Proteins/metabolism , Methanobacteriaceae/enzymology , Methionine Sulfoxide Reductases/chemistry , Methionine Sulfoxide Reductases/metabolism , Amino Acid Sequence , Catalytic Domain , Methanobacteriaceae/chemistry , Methanobacteriaceae/metabolism , Methionine/metabolism , Models, Molecular , Molecular Sequence Data , Nuclear Magnetic Resonance, Biomolecular , Oxidation-Reduction , Protein Structure, Secondary , Protein Structure, Tertiary , Sequence Alignment
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