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(American Journal of Pathology. 2002;160:1887-1894.)
© 2002 American Society for Investigative Pathology

Regular Articles

Caspase-3-Dependent Cleavage of the Glutamate-L-Cysteine Ligase Catalytic Subunit during Apoptotic Cell Death

Christopher C. Franklin*, Cecile M. Krejsa{dagger}, Robert H. Pierce{ddagger}, Collin C. White{dagger}, Nelson Fausto* and Terrance J. Kavanagh{dagger}

From the Departments of Pathology*and Environmental Health,{dagger}University of Washington, Seattle, Washington; and the Department of Pathology and Laboratory Medicine,{ddagger}University of Rochester, Rochester, New York

Apoptotic cell death is usually accompanied by activation of a family of cysteine proteases termed caspases. Caspases mediate the selective proteolysis of multiple cellular targets often resulting in the disruption of survival pathways. Intracellular levels of the antioxidant glutathione (GSH) are an important determinant of cellular susceptibility to apoptosis. The rate-limiting step in GSH biosynthesis is mediated by glutamate-L-cysteine ligase (GCL), a heterodimeric enzyme consisting of a catalytic (GCLC) and a modifier (GCLM) subunit. In this report we demonstrate that GCLC is a direct target for caspase-mediated cleavage in multiple models of apoptotic cell death. Mutational analysis revealed that caspase-mediated cleavage of GCLC occurs at Asp499 within the sequence AVVD499G. GCLC cleavage occurs upstream of Cys553, which is thought to be important for association with GCLM. GCLC cleavage is accompanied by a rapid loss of intracellular GSH due to caspase-mediated extrusion of GSH from the cell. However, while GCLC cleavage is dependent on caspase-3, GSH extrusion occurs by a caspase-3-independent mechanism. Our identification of GCLC as a target for caspase-3-dependent cleavage during apoptotic cell death suggests that this post-translational modification may represent a novel mechanism for regulating GSH biosynthesis during apoptosis.




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