Cytokine-induced SH2-containing protein (CISH)

Cytokine-induced SH2-containing protein (CISH) is a member of the suppressor of cytokine signaling (SOCS) family that plays a critical role in regulating the immune response. It acts as a negative feedback regulator of the JAK-STAT signaling pathway by binding to phosphorylated tyrosine residues on cytokine receptors, thereby blocking the recruitment of STAT transcription factors or targeting the receptors for proteasomal degradation (UniProt Q9NSE2). CISH is particularly significant in natural killer (NK) cells and T cells, where it limits their activation and effector functions in response to cytokines like IL-15 (PubMed 26996308). In the context of oncology, CISH is an emerging checkpoint target; its deletion or inhibition enhances the anti-tumor activity of immune cells, making it a focal point for next-generation cell therapies such as CRISPR-edited CAR-NK cells (e.g., FT538). Beyond cancer, genetic variants in the CISH gene have been associated with susceptibility to various infectious diseases, including tuberculosis and malaria, by modulating the host's cytokine-driven immune response (PubMed 20484392).

Other names

CISCIS-1SOCSG18BACTS2Suppressor of cytokine signaling

CISH acts as a negative regulator of cytokine signaling by binding to phosphorylated tyrosine residues on cytokine receptors (e.g., IL-15R, GHR) via its SH2 domain, which prevents STAT activation and recruits the Elongin B/C-Cullin5 E3 ubiquitin ligase complex to trigger proteasomal degradation of the signaling components (UniProt Q9NSE2; PubMed 26996308).