Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-29136-4
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Funding
- German Research Foundation [201269156, 239283807, 426018126, 400324123, BE 1540/23-2]
- LMUExcellent (Junior Researcher Fund)
- Munich Centre for NanoScience initiative (CeNS)
- Karolinska Institutet
- Knut and Alice Wallenberg Foundations
- Swedish Cancer Society
- Swedish Research Council
- Hungarian Thematic Excellence Programme [TKP2020-NKA-26]
- Studienstiftung des deutschen Volkes
- Fonds der Chemischen Industrie
- Joachim Herz Foundation
- [GRK 2338]
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The study reveals that 1,2-dithiolane probes are nonspecifically reduced by a range of thiol reductants and are not sensitive to TrxR modulation, thus they are unsuitable as cellular probes for TrxR.
The cyclic five-membered disulfide 1,2-dithiolane has been widely used in chemical biology and in redox probes. Contradictory reports have described it either as nonspecifically reduced in cells, or else as a highly specific substrate for thioredoxin reductase (TrxR). Here we show that 1,2-dithiolane probes, such as TRFS probes, are nonspecifically reduced by thiol reductants and redox-active proteins, and their cellular performance is barely affected by TrxR inhibition or knockout. Therefore, results of cellular imaging or inhibitor screening using 1,2-dithiolanes should not be interpreted as reflecting TrxR activity, and previous studies may need re-evaluation. To understand 1,2-dithiolanes' complex behaviour, probe localisation, environment-dependent fluorescence, reduction-independent ring-opening polymerisation, and thiol-dependent cellular uptake must all be considered; particular caution is needed when co-applying thiophilic inhibitors. We present a general approach controlling against assay misinterpretation with reducible probes, to ensure future TrxR-targeted designs are robustly evaluated for selectivity, and to better orient future research. Cyclic five-membered disulfides (1,2-dithiolanes) have been reported either as nonspecific redox motifs, or as highly specific cellular probes for thioredoxin reductase (TrxR). Here the authors show that 1,2-dithiolane probes are nonspecifically reduced by a range of thiol reductants and are not sensitive to TrxR modulation, thus they are unsuitable as cellular probes for TrxR.
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