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Superoxide dismutase protects calcineurin from inactivation

X Wang¹, V C Culotta, C B Klee

¹Laboratory of Biochemistry, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA.

|October 3, 1996

Abstract:

Calcineurin is the only protein phosphatase known to be under the control of Ca2+ and calmodulin. It is targeted by immunosuppressive drugs and has a critical role in T-cell activation. It is specifically inhibited by immunosuppressant immunophilin complexes, which enabled its function in regulating a wide range of cellular responses to Ca2+-mobilizing signals to be identified. Calcineurin in situ is 10-20 times more active than in the purified form and is subject to a time- and Ca2+/calmodulin-dependent reversible inactivation that is facilitated by small, heat-stable molecules. Here we identify a factor that prevents the inactivation of calcineurin in vitro and in vivo as the enzyme superoxide dismutase, which indicates that inactivation may be the result of oxidative damage to the Fe-Zn active centre of calcineurin. The redox state of iron provides a mechanism to regulate calcineurin activity by desensitizing the enzyme and coupling Ca2+-dependent protein dephosphorylation to the redox state of the cell. The protection of calcineurin against inactivation by superoxide dismutase constitutes a new physiological role for this enzyme which enables the Ca2+-dependent regulation of cellular processes to be modulated by the redox potential.

Insights

Superoxide dismutase protects calcineurin, a key enzyme in T-cell activation, from oxidative damage. This finding reveals a new role for superoxide dismutase in regulating cellular responses by linking calcium signaling to cellular redox state.

Area of Science:

Biochemistry
Cell Biology
Immunology

Background:

Calcineurin is a calcium/calmodulin-dependent protein phosphatase crucial for T-cell activation.
Its activity is regulated by Ca2+ and calmodulin, and it's a target for immunosuppressive drugs.
In situ, calcineurin is more active and undergoes reversible inactivation, influenced by heat-stable molecules.

Purpose of the Study:

To identify the factor responsible for preventing calcineurin inactivation in vitro and in vivo.
To elucidate the mechanism of calcineurin inactivation and its regulation.
To explore the physiological role of superoxide dismutase in calcineurin regulation.

Main Methods:

In vitro and in vivo experiments were conducted.
Identification of a heat-stable molecule that prevents calcineurin inactivation.
Analysis of the effect of superoxide dismutase on calcineurin activity and stability.

Main Results:

Superoxide dismutase was identified as the factor preventing calcineurin inactivation.
Calcineurin inactivation is proposed to result from oxidative damage to its Fe-Zn active center.
The redox state of iron in calcineurin regulates its activity and couples dephosphorylation to cellular redox state.

Conclusions:

Superoxide dismutase plays a novel physiological role in protecting calcineurin from oxidative inactivation.
This protection mechanism allows cellular redox potential to modulate Ca2+-dependent signaling pathways.
Calcineurin activity is regulated by both calcium levels and the cell's redox environment.

Read full analysis

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