CISH (protein)
Cytokine-inducible SH2-containing protein is a protein that in humans is encoded by the CISH gene. CISH orthologs have been identified in most mammals with sequenced genomes. CISH controls T cell receptor signaling, and variations of CISH with certain SNPs are associated with susceptibility to bacteremia, tuberculosis and malaria.
Function
The protein encoded by this gene contains a SH2 domain and a SOCS box domain. The protein thus belongs to the cytokine-induced STAT inhibitor, also known as suppressor of cytokine signaling or STAT-induced STAT inhibitor, protein family. CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling.The expression of this gene can be induced by IL-2, IL-3, GM-CSF and EPO in hematopoietic cells. Proteasome-mediated degradation of this protein has been shown to be involved in the inactivation of the erythropoietin receptor.
CISH is induced by T cell receptor ligation and negatively regulates it by targeting the critical signaling intermediate PLC-gamma-1 for degradation. The deletion of Cish in effector T cells has been shown to augment TCR signaling and subsequent effector cytokine release, proliferation and survival. The adoptive transfer of tumor-specific effector T cells knocked out or knocked down for CISH resulted in a significant increase in functional avidity and long-term tumor immunity. There are no changes in activity or phosphorylation of Cish's purported target, STAT5 in either the presence or absence of Cish.
In human tumor-infiltrating lymphocytes, CISH expression has been reported to be inversely expressed with known T cell activation/exhaustion markers and regulates their expression and neoantigen reactivity. Combination therapy with checkpoint blockade synergistically results in profound tumor regressing in a pre-clinical tumor model