The role of thioredoxin in the redox regulation of the Tpx1/Pap1 pathway in Schizosaccharomyces pombe.
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Date
2022
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Abstract
Reactive oxygen species (ROS) can damage cellular components leading to dysfunction and
cell death. Paradoxically, ROS, such as hydrogen peroxide, are also essential for a range of
metabolic and signalling functions within cells. Given these opposing functions, cells have
developed several redox signalling mechanisms to manage ROS within specific homeostatic
limits. In bacterial cells, thiol-peroxidases (peroxiredoxins) and other enzymes detoxify ROS,
while the antioxidant transcriptional response is induced by transcription factors directly oxidized
by ROS. In many eukaryotes, these functions are combined with peroxiredoxins detoxifying ROS
as well as activating redox-sensitive transcription factors. The relative benefits and disadvantages
of such sensor-mediated redox signalling systems are unknown, and we aimed to understand the
logic underlying this signalling mechanism using the Schizosaccharomyces pombe Tpx1/Pap1
pathway. In this pathway, the peroxiredoxin Tpx1 reduces hydrogen peroxide and oxidizes the
redox transcription factor Pap1. Following a hydrogen peroxide perturbation, the Pap1 signal
profile revealed a biphasic profile with a rapid initial increase followed by a relatively prolonged
decrease in Pap1 oxidation. These dynamics were suggestive of an incoherent feedforward loop,
and we hypothesized that the Trx1 protein was responsible for the incoherence as it could both
dampen and increase the signal by reducing Pap1 and Tpx1, respectively. To test this hypothesis,
we analyzed the effect of several oxidants (hydrogen peroxide, tert-butyl hydroperoxide, and
diamide) on Pap1 activation to determine if we could selectively modulate signal duration.
However, we could not quantitatively delineate the effects of these oxidants on the signal profiles
obtained. We, therefore, utilized computational modelling to analyze the Tpx1/Pap1 pathway and
found that excess Trx1 reduced Tpx1 faster, preventing the association of Tpx1 and Pap1. On the
other hand, insufficient Trx1 allowed for Pap1 to be oxidized over a longer interval which
increased the signal duration. Thus, our analysis showed that, in contrast to our hypothesis, Trx1
limitation, rather than incoherence, was responsible for the Pap1 oxidation profile. These results
indicate that in the presence of ROS, Trx1 plays a vital role in determining the signal profile of
Pap1.
Description
Masters Degree. University of KwaZulu-Natal, Pietermaritzburg.