Cytokine-inducible SH2-containing protein is a protein that in humans is encoded by the CISH gene. [5] [6] [7] CISH orthologs [8] have been identified in most mammals with sequenced genomes. CISH controls T cell receptor (TCR) signaling, and variations of CISH with certain SNPs are associated with susceptibility to bacteremia, tuberculosis and malaria. [9]
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 (CIS), also known as suppressor of cytokine signaling (SOCS) or STAT-induced STAT inhibitor (SSI), 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. [7]
CISH is induced by T cell receptor (TCR) ligation and negatively regulates it by targeting the critical signaling intermediate PLC-gamma-1 for degradation. [10] 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 (TIL), 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 synergestically results in profound tumor regressing in a pre-clinical tumor model [11]
| Characteristic | Phenotype |
|---|---|
| Homozygote viability | Normal |
| Fertility | Normal |
| Body weight | Normal |
| Anxiety | Normal |
| Neurological assessment | Normal |
| Grip strength | Normal |
| Hot plate | Normal |
| Dysmorphology | Normal |
| Indirect calorimetry | Normal |
| Glucose tolerance test | Normal |
| Auditory brainstem response | Normal |
| DEXA | Normal |
| Radiography | Normal |
| Body temperature | Normal |
| Eye morphology | Normal |
| Clinical chemistry | Normal |
| Haematology | Normal |
| Peripheral blood lymphocytes | Normal |
| Micronucleus test | Normal |
| Heart weight | Normal |
| Skin Histopathology | Normal |
| Eye Histopathology | Normal |
| Salmonella infection | Normal [12] |
| Citrobacter infection | Normal [13] |
| All tests and analysis from [14] [15] |
Model organisms have been used in the study of CISH function. A conditional knockout mouse line, called Cishtm1a(KOMP)Wtsi [16] [17] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute. [18] [19] [20]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. [14] [21] Twenty four tests were carried out on mutant mice, however no significant abnormalities were observed. [14]
CISH has been shown to interact with IL2RB [22] and Growth hormone receptor. [23] and PLCG1. [10]
Interleukin 33 (IL-33) is a protein that in humans is encoded by the IL33 gene.
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Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1.
Suppressor of cytokine signaling 6 is a protein that in humans is encoded by the SOCS6 gene.
Ubiquitin carboxyl-terminal hydrolase 20 is an enzyme that in humans is encoded by the USP20 gene.
A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases are a subgroup of protein family tyrosine kinases, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell.
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