Oncotarget

Research Papers: Immunology:

A highly conserved redox-active Mx(2)CWx(6)R motif regulates Zap70 stability and activity

Christoph Thurm, Mateusz P. Poltorak, Elisa Reimer, Melanie M. Brinkmann, Lars Leichert, Burkhart Schraven and Luca Simeoni _

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Oncotarget. 2017; 8:30805-30816. https://doi.org/10.18632/oncotarget.16486

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Abstract

Christoph Thurm1, Mateusz P. Poltorak1,5, Elisa Reimer2, Melanie M. Brinkmann2, Lars Leichert3, Burkhart Schraven1,4 and Luca Simeoni1

1 Institute of Molecular and Clinical Immunology, Health Campus Immunology, Infectiology, and Inflammation, Otto von Guericke University, Magdeburg, Germany

2 Viral Immune Modulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany

3 Institute for Biochemistry and Pathobiochemistry, Ruhr University, Bochum, Germany

4 Department of Immune Control, Helmholtz Centre for Infection Research, Braunschweig, Germany

5 Current address: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany

Correspondence to:

Luca Simeoni, email:

Keywords: Zap70, oxidation, TCR signaling, Cdc37, protein stability, Immunology and Microbiology Section, Immune response, Immunity

Received: January 12, 2017 Accepted: March 16, 2017 Published: March 22, 2017

Abstract

ζ-associated protein of 70 kDa (Zap70) is crucial for T-cell receptor (TCR) signaling. Loss of Zap70 in both humans and mice results in severe immunodeficiency. On the other hand, the expression of Zap70 in B-cell malignancies correlates with the severity of the disease. Because of its role in immune-related disorders, Zap70 has become a therapeutic target for the treatment of human diseases. It is well-established that the activity/expression of Zap70 is regulated by post-translational modifications of crucial amino acids including the phosphorylation of tyrosines and the ubiquitination of lysines. Here, we have investigated whether also oxidation of cysteine residues regulates Zap70 functions. We have identified C575 as a major sulfenylation site of Zap70. A C575A substitution results in protein instability, reduced activity, and increased dependency on the Hsp90/Cdc37 chaperone system. Indeed, Cdc37 overexpression reconstituted partially the expression but fully the function of Zap70C575A. C575 lies within a Mx(2)CWx(6)R motif which is highly conserved among almost all human tyrosine kinases. Mutation of any of the conserved amino acids, but not of a non-conserved residue preceding the cysteine, also results in Zap70 instability. Collectively, we have identified a new redox-active motif which is crucial for the regulation of Zap70 stability/activity. We believe that this motif has the potential to become a novel target for the development of therapeutic tools to modulate the expression/activity of kinases.


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