The Sts proteins target tyrosine phosphorylated, ubiquitinated proteins within TCR signaling pathways.
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.
Carpino
Nick
N
Department of Molecular Genetics and Microbiology, Room 130, Life Sciences Building, Stony Brook University, Stony Brook, NY 11794-5222, USA. ncarpino@notes.cc.sunysb.edu
Chen
Yunting
Y
Nassar
Nicolas
N
Oh
Hye-Won
HW
D000818:Animals; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D017027:Protein Tyrosine Phosphatases; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014443:Tyrosine / Q000235:genetics / Q000276:immunology; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology*
D011948:Receptors, Antigen, T-Cell; C482177:Sts-2 protein, mouse; D014443:Tyrosine; D017027:Protein Tyrosine Phosphatases; C553497:TULA-2 protein, mouse