The Sts proteins target tyrosine phosphorylated, ubiquitinated proteins within TCR signaling pathways

• Published in: Molecular immunology 2009-10, Vol.46 (16), p.3224-3231
• Main Authors: Carpino, Nick, Chen, Yunting, Nassar, Nicolas, Oh, Hye-Won
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; BASIC BIOLOGICAL SCIENCES; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; MICE; Mice, Knockout; national synchrotron light source; PATHOGENS; PHOSPHATASES; PHOSPHORYLATION; Phosphorylation - genetics; Phosphorylation - immunology; Protein Tyrosine Phosphatases; PROTEINS; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; REGULATIONS; Signal transduction; Signal Transduction - genetics; Signal Transduction - immunology; STIMULATION; T cell activation; T cell phosphatase; T cells; T-Lymphocytes - immunology; TARGETS; TYROSINE; Tyrosine - genetics; Tyrosine - immunology; Ubiquitination; Ubiquitination - genetics; Ubiquitination - immunology
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2009.08.015

The T cell receptor (TCR) detects the presence of infectious pathogens and activates numerous intracellular signaling pathways. Protein tyrosine phosphorylation and ubiquitination serve as key regulatory mechanisms downstream of the TCR. Negative regulation of TCR signaling pathways is important in controlling the immune response, and the Suppressor of TCR Signaling proteins (Sts-1 and Sts-2) have been shown to function as critical negative regulators of TCR signaling. Although their mechanism of action has yet to be fully uncovered, it is known that the Sts proteins possess intrinsic phosphatase activity. Here, we demonstrate that Sts-1 and Sts-2 are instrumental in down-modulating proteins that are dually modified by both protein tyrosine phosphorylation and ubiquitination. Specifically, both naïve and activated T cells derived from genetically engineered mice that lack the Sts proteins display strikingly elevated levels of tyrosine phosphorylated, ubiquitinated proteins following TCR stimulation. The accumulation of the dually modified proteins is transient, and in activated T cells but not naïve T cells is significantly enhanced by co-receptor engagement. Our observations hint at a novel regulatory mechanism downstream of the T cell receptor.