{"gene":"CISH","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1995,"finding":"CIS (cytokine-inducible SH2-containing protein / CISH) was identified as a novel cytokine-inducible immediate-early gene encoding a 257-amino acid SH2-domain-containing protein that stably associates with the tyrosine-phosphorylated beta chain of the IL-3 receptor and the tyrosine-phosphorylated EPO receptor, and forced expression of CIS reduced growth rate of hematopoietic cell lines, demonstrating a negative regulatory role in cytokine signal transduction.","method":"Co-immunoprecipitation, steroid-inducible expression system in IL-3-dependent hematopoietic cell lines, proliferation assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding demonstrated with multiple receptor targets, functional readout via growth inhibition, foundational discovery paper with >630 citations","pmids":["7796808"],"is_preprint":false},{"year":1998,"finding":"CIS associates with the second tyrosine residue (Tyr401) of the intracellular domain of the erythropoietin receptor. CIS exists in two forms (32 kDa and 37 kDa); the 37-kDa form is ubiquitinated and rapidly degraded by the proteasome. Proteasome inhibitors caused accumulation of ubiquitinated CIS and CIS-EPO receptor complexes, and also prolonged EPO receptor and STAT5 phosphorylation, implicating ubiquitinated CIS in proteasome-mediated inactivation of EPO receptor signaling.","method":"Co-immunoprecipitation, anti-ubiquitin immunoblotting, proteasome inhibitor treatment (ALLN, lactacystin), Western blot of receptor/STAT5 phosphorylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical methods, ubiquitination directly demonstrated, functional consequence of proteasome inhibition shown","pmids":["9774439"],"is_preprint":false},{"year":1999,"finding":"CIS associates with the IL-2 receptor beta chain (IL-2Rbeta) via the A region (residues 313–382), inhibiting Lck-mediated phosphorylation of IL-2Rbeta and IL-2-mediated STAT5 activation. A dominant-negative CIS mutant with an altered SH2 domain confirmed that the phosphotyrosine-binding capability of the SH2 domain is essential for CIS inhibitory function.","method":"Co-immunoprecipitation, in vitro binding assays, transfection with wild-type and SH2 mutant CIS, STAT5 activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, mutagenesis of SH2 domain to generate dominant negative, multiple signaling readouts","pmids":["10514520"],"is_preprint":false},{"year":1999,"finding":"CIS inhibits growth hormone (GH)-stimulated STAT5b activation and STAT5b-dependent transcription by binding to membrane-distal tyrosine residues on the GH receptor (GHR) in a tyrosine-phosphorylation-dependent manner, a mechanism distinct from SOCS-1 (direct JAK2 inhibition) and SOCS-3 (membrane-proximal GHR tyrosines). CIS binding required tyrosine-phosphorylated GHR membrane-distal sequences; SOCS-2 behaved similarly.","method":"GST-GHR fusion protein in vitro binding assays, transfection in COS cells, STAT5b reporter assays, JAK2 phosphorylation assays, GHR tyrosine mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding assays with defined GHR deletion/mutation series, multiple SOCS family members compared, functional transcriptional readout","pmids":["10585430"],"is_preprint":false},{"year":2001,"finding":"CIS suppresses PRL (prolactin) signaling by associating with the PRL receptor (PRLR) and inhibiting STAT5 activation, by a mechanism downstream of and distinct from SOCS-1's inhibition of JAK2. CIS produced ~70% inhibition of PRL-stimulated beta-casein promoter activity; this inhibition required PRLR association.","method":"Co-immunoprecipitation, transfection in HEK293 cells, beta-casein promoter luciferase reporter assay, STAT5 activation assay","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 — Co-IP demonstrating PRLR association, functional reporter assay, comparison with other SOCS family members","pmids":["11713228"],"is_preprint":false},{"year":2003,"finding":"IL-6 inhibits hepatic GH signaling by inducing upregulation of both CIS and SOCS-3 protein through STAT3 activation. In IL-6 knockout mice, LPS-induced suppression of GH-stimulated STAT5 activation was abrogated, and CIS and SOCS-3 were not induced, establishing CIS as part of the IL-6/STAT3-mediated negative feedback on GH/STAT5 signaling in the liver.","method":"IL-6 and TNFR1 knockout mouse models, LPS administration, immunoblot for STAT5/STAT3 phosphorylation and CIS/SOCS-3 protein levels, real-time RT-PCR, ELISA","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis using knockout mice, multiple orthogonal methods, specific phenotypic rescue","pmids":["12519742"],"is_preprint":false},{"year":2008,"finding":"The SOCS box of CIS can function as a modulator of substrate binding, representing a distinct role compared to other SOCS box functions. This places CIS as using the SOCS box not only for E3 ligase recruitment but also for altering its own substrate-binding properties.","method":"Structural/biochemical analysis reviewed with experimental data","journal":"Cytokine & growth factor reviews","confidence":"Low","confidence_rationale":"Tier 4 — review paper citing experimental work; the specific experimental basis for CIS SOCS box modulating substrate binding is not directly described in an included primary paper","pmids":["18948053"],"is_preprint":false},{"year":2008,"finding":"RACK1 forms a complex with DLC1 and BimEL (a pro-apoptotic protein), and CIS mediates the degradation of BimEL through an ElonginB/C–Cullin2–CIS ubiquitin-protein isopeptide ligase (E3) complex upon paclitaxel treatment. An inverse correlation between CIS and BimEL levels was observed in ovarian and breast cancer cell lines and specimens.","method":"Yeast two-hybrid (identification of RACK1 partners), co-immunoprecipitation, ubiquitination assay with ElonginB/C-Cullin2-CIS complex, Western blot, in vitro and in vivo cancer cell studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct ubiquitination assay demonstrating CIS as E3 ligase adaptor for BimEL, multiple orthogonal methods including Co-IP and in vivo validation","pmids":["18420585"],"is_preprint":false},{"year":2009,"finding":"CIS expression in cholangiocytes is post-transcriptionally regulated by microRNA-98 (miR-98) and let-7, which target the 3'-UTR of CIS mRNA for translational repression without mRNA degradation. LPS stimulation or Cryptosporidium parvum infection decreased miR-98 and let-7 levels, relieving CIS translational repression and increasing CIS protein. CIS in turn enhanced IκBα degradation and regulated NF-κB activation in cholangiocytes.","method":"Luciferase reporter assay with CIS 3'-UTR, miRNA overexpression/knockdown, CIS siRNA and overexpression, NF-κB activation assays, Western blot","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — direct 3'-UTR targeting demonstrated by luciferase assay and miRNA manipulation, functional consequence on NF-κB shown by gain- and loss-of-function","pmids":["19592657"],"is_preprint":false},{"year":2010,"finding":"CISH polymorphisms in the promoter region are associated with susceptibility to bacteremia, tuberculosis, and severe malaria. The -292 variant reduced CISH expression by 25–40% in peripheral blood mononuclear cells stimulated to produce IL-2, demonstrating that CISH controls interleukin-2 signaling and that its expression level determines host resistance to infectious diseases.","method":"Case-control association study, functional PBMC stimulation assays measuring CISH mRNA levels by genotype","journal":"The New England journal of medicine","confidence":"Medium","confidence_rationale":"Tier 3 — functional PBMC assay supporting promoter variant effect on CISH expression; primary genetic association; mechanism inferred from expression data","pmids":["20484391"],"is_preprint":false},{"year":2011,"finding":"CISH is induced during dendritic cell (DC) development from bone marrow cells and plays a role in type 1 DC development and DC-mediated CTL activation. CISH knockdown increased DC yield (via cell-cycle activation and reduced apoptosis) but reduced MHC class I, co-stimulatory molecule expression, pro-inflammatory cytokines, and impaired CTL priming. CISH-mediated negative feedback on STAT5 activation terminates DC progenitor proliferation and promotes DC differentiation into CTL stimulators.","method":"CISH knockdown in bone marrow-derived DCs, flow cytometry, cell cycle analysis, STAT5 phosphorylation assay, T cell proliferation assay, tumor immunotherapy model","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 — defined cellular phenotype with STAT5 mechanistic link, multiple functional readouts, single lab","pmids":["22002016"],"is_preprint":false},{"year":2011,"finding":"CISH (CIS) associates with the IL-2 receptor complex and regulates Treg expansion induced by Mycobacterium tuberculosis. PD-1 siRNA inhibited CISH expression in expanded Tregs, placing CIS downstream of PD-1 in the M. tuberculosis-induced Treg expansion pathway. CISH siRNA and anti-PD-1 siRNA each blocked M. tuberculosis-stimulated Treg expansion from CD4+CCR4+ cells.","method":"siRNA knockdown of PD-1 and CISH, flow cytometry for Treg expansion, cytokine measurement (TGF-β, IL-10, IFN-γ)","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 3 — siRNA functional data with defined cellular phenotype; pathway placement by epistasis (PD-1 upstream of CISH)","pmids":["21383382"],"is_preprint":false},{"year":2017,"finding":"M. tuberculosis infection of macrophages induces GM-CSF secretion, which triggers STAT5-mediated expression of CISH; CISH then selectively targets the V-ATPase catalytic subunit A (ATP6V1A) for ubiquitination and proteasomal degradation, impairing phagosomal acidification and promoting mycobacterial survival. Inhibition of CISH expression reduced M. tuberculosis replication in macrophages.","method":"Macrophage infection models, CISH knockdown/inhibition, ubiquitination assay, V-ATPase subunit localization and abundance assays, bacterial replication assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — direct ubiquitination of ATP6V1A by CISH demonstrated, functional consequence (phagosomal acidification, bacterial replication) confirmed by loss-of-function","pmids":["28954234"],"is_preprint":false},{"year":2020,"finding":"CIS (CISH) negatively regulates GM-CSF receptor signaling in NK cells. CIS-deficient NK cells displayed enhanced GM-CSF-driven signaling, and CISH deletion in NK cells exacerbated autoantibody-mediated inflammatory arthritis and experimental allergic encephalomyelitis, demonstrating that endogenous CIS provides a key brake on GM-CSF receptor-mediated NK cell activation.","method":"CIS knockout mouse models, GM-CSF fate reporter mice, cytokine production assays, NK cell-specific GM-CSF deletion, disease models (arthritis, EAE)","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with specific receptor signaling pathway (GM-CSFR), multiple in vivo disease models, cell-specific deletion","pmids":["32097462"],"is_preprint":false},{"year":2023,"finding":"CISH expression is elevated in T cells from older adults and impairs lysosomal function by targeting ATP6V1A (V-ATPase proton pump catalytic subunit) for proteasomal degradation. Impaired lysosomal activity leads to accumulation of multivesicular bodies and amphisomes and export of mitochondrial DNA (mtDNA) into the environment, contributing to inflammaging. CISH silencing in T cells from older adults restored lysosomal activity and prevented amphisomal mtDNA release.","method":"CISH overexpression and siRNA knockdown in T cells, lysosomal activity assays, V-ATPase subunit abundance measurement, multivesicular body/amphisome imaging, mtDNA release assay, in vivo antigen-specific response in CISH-deficient CD4+ T cells","journal":"Nature aging","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway (CISH → ATP6V1A degradation → lysosomal failure → amphisomal mtDNA release) validated by multiple orthogonal methods and in vivo confirmation","pmids":["37118554"],"is_preprint":false},{"year":2020,"finding":"miR-944 directly targets CISH mRNA, downregulating CISH protein in oral squamous cell carcinoma (OSCC). Loss of CISH leads to increased STAT3 phosphorylation, pro-inflammatory cytokine secretion, and enhanced cell migration and invasion; restoration of CISH abolished these oncogenic effects of miR-944, placing CISH as a direct post-transcriptional target of miR-944 that modulates STAT3 activity.","method":"Luciferase reporter assay (3'-UTR targeting), qRT-PCR, immunohistochemistry, gain- and loss-of-function (miR-944 and CISH), transwell migration/invasion assay, ELISA for cytokines","journal":"Neoplasia","confidence":"High","confidence_rationale":"Tier 2 — direct 3'-UTR targeting validated by luciferase assay, rescue experiment showing CISH-dependent phenotype, multiple functional readouts","pmids":["32961483"],"is_preprint":false},{"year":2014,"finding":"CISH promoter polymorphisms (rs414171 and rs809451) alter CISH transcriptional activity; the G(-809451)-A(-414171)-C(-622502) haplotype drove 5.43-fold higher reporter expression compared to the risk haplotype. PBMCs carrying rs414171TT showed reduced CISH mRNA and increased IL-12p40 and IL-10 production, demonstrating that CISH promoter variants functionally regulate CISH expression and downstream cytokine responses in the context of TB susceptibility.","method":"Luciferase reporter assay (promoter variants), qRT-PCR of CISH mRNA in PBMCs, ELISA for IL-12p40 and IL-10, case-control genotyping","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — promoter function demonstrated by reporter assay, cytokine consequence measured; primarily genetic association study with functional follow-up","pmids":["24632804"],"is_preprint":false}],"current_model":"CISH (CIS) is a cytokine-inducible SH2-domain-containing protein that functions as a negative feedback inhibitor of cytokine signaling by: (1) binding tyrosine-phosphorylated cytokine receptors (IL-2Rβ, EPO-R, GHR, PRLR, GM-CSFR) via its SH2 domain to block STAT5 activation; (2) acting as a substrate-recognition adaptor for an ElonginB/C–Cullin2–CISH E3 ubiquitin ligase complex to target specific substrates (BimEL, ATP6V1A/V-ATPase subunit A) for proteasomal degradation; (3) being itself rapidly ubiquitinated and proteasomally degraded to limit its own accumulation; and (4) having its expression post-transcriptionally regulated by miR-98, let-7, and miR-944, while its transcription is driven by STAT5 in response to IL-2 and GM-CSF stimulation, creating a classic negative feedback loop."},"narrative":{"teleology":[{"year":1995,"claim":"The discovery of CISH as a cytokine-inducible SH2-containing protein that binds phosphorylated IL-3Rβ and EPO-R and suppresses hematopoietic cell growth established it as a new class of negative feedback regulator of cytokine signaling.","evidence":"Co-immunoprecipitation and steroid-inducible expression in IL-3-dependent cell lines with proliferation assays","pmids":["7796808"],"confidence":"High","gaps":["Molecular mechanism of growth suppression unknown","Receptor specificity beyond IL-3R and EPO-R uncharacterized","Relationship to other SH2-domain inhibitors (SOCS family) undefined"]},{"year":1998,"claim":"Demonstration that CISH is ubiquitinated and rapidly degraded by the proteasome—and that blocking proteasomal degradation prolongs EPO-R/STAT5 signaling—revealed a self-limiting regulatory circuit in which CISH's own turnover controls signaling duration.","evidence":"Anti-ubiquitin immunoblotting, proteasome inhibitor treatment (ALLN, lactacystin), phosphorylation kinetics of EPO-R and STAT5","pmids":["9774439"],"confidence":"High","gaps":["E3 ligase responsible for CISH ubiquitination not identified","Whether CISH ubiquitination targets receptor complexes for co-degradation not resolved"]},{"year":1999,"claim":"Mapping CISH's SH2-dependent binding to IL-2Rβ and to membrane-distal phosphotyrosines on GHR, and showing that this blocks STAT5 activation without inhibiting JAK2 directly, defined a receptor-proximal competitive mechanism distinct from SOCS-1/SOCS-3.","evidence":"Co-IP with IL-2Rβ deletion mutants, SH2-domain dominant-negative mutant, GST-GHR fusion binding assays, STAT5b reporter assays","pmids":["10514520","10585430"],"confidence":"High","gaps":["Structural basis for selective phosphotyrosine recognition not determined","Stoichiometry of CISH at native receptor complexes unknown"]},{"year":2001,"claim":"Extension to the prolactin receptor showed CISH inhibits PRL/STAT5 signaling by associating with PRLR, broadening the model to include a role in lactation-related cytokine pathways.","evidence":"Co-IP in HEK293 cells, beta-casein promoter luciferase reporter","pmids":["11713228"],"confidence":"High","gaps":["In vivo relevance for mammary gland biology not tested","Binding site on PRLR not mapped"]},{"year":2003,"claim":"IL-6/STAT3-driven induction of CISH in liver established a cross-cytokine regulatory axis in which inflammatory IL-6 signaling suppresses GH/STAT5 signaling through CISH upregulation, providing in vivo evidence from IL-6-knockout mice.","evidence":"IL-6 and TNFR1 knockout mice, LPS challenge, immunoblot for STAT5/STAT3 phosphorylation and CIS protein","pmids":["12519742"],"confidence":"High","gaps":["Relative contributions of CISH versus SOCS-3 to GH resistance not separated genetically","Tissue-specific regulation beyond liver unexplored"]},{"year":2008,"claim":"Identification of CISH as the substrate adaptor of an ElonginB/C–Cullin2 E3 ligase complex that ubiquitinates the pro-apoptotic protein BimEL established a second molecular activity for CISH beyond receptor competition—direct substrate targeting for degradation.","evidence":"Yeast two-hybrid, co-IP, in vitro ubiquitination reconstitution with ElonginB/C-Cullin2-CIS, cancer cell line and specimen correlation","pmids":["18420585"],"confidence":"High","gaps":["Full substrate repertoire of the Cullin2-CISH E3 ligase unknown","Structural basis for BimEL recognition not determined"]},{"year":2009,"claim":"Discovery that miR-98 and let-7 post-transcriptionally repress CISH by targeting its 3′-UTR, and that CISH in turn promotes IκBα degradation and NF-κB activation, revealed a previously unknown miRNA-regulated layer of CISH control and an unexpected connection to innate immune NF-κB signaling.","evidence":"Luciferase 3′-UTR reporter, miRNA overexpression/knockdown, NF-κB activation assays in cholangiocytes upon LPS and C. parvum infection","pmids":["19592657"],"confidence":"High","gaps":["Mechanism linking CISH to IκBα degradation not elucidated","Generalizability of miR-98/let-7 regulation to immune cell types not shown"]},{"year":2011,"claim":"CISH's role was extended to immune cell differentiation: it terminates STAT5-driven DC progenitor proliferation and promotes type-1 DC maturation required for CTL priming, and it participates in PD-1-dependent Treg expansion during M. tuberculosis infection.","evidence":"CISH knockdown in bone-marrow-derived DCs with flow cytometry and CTL priming assays; PD-1 and CISH siRNA epistasis in M. tuberculosis-stimulated Treg expansion","pmids":["22002016","21383382"],"confidence":"Medium","gaps":["Whether CISH is required for DC differentiation in vivo not demonstrated with conditional knockout","Mechanism of PD-1-driven CISH induction in Tregs not defined biochemically"]},{"year":2017,"claim":"CISH was shown to be exploited by M. tuberculosis: GM-CSF/STAT5-induced CISH targets V-ATPase subunit ATP6V1A for ubiquitin-dependent degradation, impairing phagosomal acidification and enabling intracellular bacterial survival.","evidence":"Macrophage infection, CISH knockdown/inhibition, ubiquitination assay for ATP6V1A, phagosomal acidification and bacterial replication measurements","pmids":["28954234"],"confidence":"High","gaps":["Whether ATP6V1A is a direct Cullin2-CISH E3 substrate or requires additional adaptors not fully resolved","Relevance to human TB macrophages in vivo not confirmed"]},{"year":2020,"claim":"Genetic deletion of CISH in NK cells revealed that CISH restrains GM-CSF receptor signaling and that its loss exacerbates autoimmune inflammation, establishing CISH as a cell-intrinsic checkpoint on NK cell activation in vivo.","evidence":"CIS-knockout and NK-cell-specific GM-CSFR-deletion mice, arthritis and EAE disease models, cytokine assays","pmids":["32097462"],"confidence":"High","gaps":["Precise signaling intermediates downstream of GM-CSFR that CISH targets in NK cells not identified","Therapeutic relevance of CISH modulation in autoimmunity not tested"]},{"year":2023,"claim":"Elevated CISH in aged T cells was linked to lysosomal failure via ATP6V1A degradation, causing amphisomal accumulation and extracellular release of mitochondrial DNA—a mechanism contributing to inflammaging—and CISH silencing rescued these defects.","evidence":"CISH overexpression/siRNA in human T cells, lysosomal activity and V-ATPase subunit assays, amphisome/mtDNA imaging, in vivo CISH-deficient CD4+ T cell responses","pmids":["37118554"],"confidence":"High","gaps":["Whether CISH-driven lysosomal dysfunction operates in non-T immune cells during aging is unknown","Upstream signals driving age-dependent CISH overexpression not identified"]},{"year":null,"claim":"A comprehensive structural model of the CISH SH2 domain in complex with phosphorylated receptor peptides and of the Cullin2–ElonginB/C–CISH E3 holoenzyme is lacking, and the full substrate repertoire of the CISH E3 ligase remains undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of CISH SH2 bound to any receptor phosphopeptide","Complete substrate catalog of Cullin2-CISH E3 ligase not established","Relative contribution of receptor-blocking versus E3-ligase activity to CISH's physiological effects not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,3,4,13]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[7,12,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,3,4,5,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,10,11,12,13,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,7,12,14]}],"complexes":["ElonginB/C–Cullin2–CISH E3 ubiquitin ligase"],"partners":["IL2RB","EPOR","GHR","PRLR","CSF2RB","ATP6V1A","BCL2L11","RACK1"],"other_free_text":[]},"mechanistic_narrative":"CISH (cytokine-inducible SH2-containing protein) is a STAT5-induced negative-feedback regulator of JAK–STAT signaling that broadly restrains cytokine responses in hematopoietic and immune cells. Its SH2 domain binds tyrosine-phosphorylated cytokine receptor chains—including IL-2Rβ, EPO-R, GHR, PRLR, and GM-CSFR—to competitively block STAT5 recruitment and activation [PMID:7796808, PMID:10514520, PMID:10585430, PMID:11713228, PMID:32097462]. Beyond receptor antagonism, CISH functions as the substrate-recognition subunit of an ElonginB/C–Cullin2 E3 ubiquitin ligase complex that targets the pro-apoptotic protein BimEL and the V-ATPase catalytic subunit ATP6V1A for proteasomal degradation, thereby regulating apoptosis and phagosomal/lysosomal acidification in macrophages and T cells [PMID:18420585, PMID:28954234, PMID:37118554]. CISH itself undergoes rapid ubiquitin-dependent proteasomal turnover and is subject to post-transcriptional repression by miR-98, let-7, and miR-944, which together fine-tune the amplitude and duration of its inhibitory activity [PMID:9774439, PMID:19592657, PMID:32961483]."},"prefetch_data":{"uniprot":{"accession":"Q9NSE2","full_name":"Cytokine-inducible SH2-containing protein","aliases":["CIS-1","Protein G18","Suppressor of cytokine signaling","SOCS"],"length_aa":258,"mass_kda":28.7,"function":"SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. CIS is involved in the negative regulation of cytokines that signal through the JAK-STAT5 pathway such as erythropoietin, prolactin and interleukin 3 (IL3) receptor. Inhibits STAT5 trans-activation by suppressing its tyrosine phosphorylation. May be a substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (By similarity)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9NSE2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CISH","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CISH","total_profiled":1310},"omim":[{"mim_id":"620532","title":"HYPER-IgE SYNDROME 6, AUTOSOMAL DOMINANT, WITH RECURRENT INFECTIONS; HIES6","url":"https://www.omim.org/entry/620532"},{"mim_id":"614383","title":"BACTEREMIA, SUSCEPTIBILITY TO, 2; BACTS2","url":"https://www.omim.org/entry/614383"},{"mim_id":"612472","title":"METHYLTRANSFERASE 3, N6-ADENOSINE-METHYLTRANSFERASE COMPLEX CATALYTIC SUBUNIT; METTL3","url":"https://www.omim.org/entry/612472"},{"mim_id":"611162","title":"MALARIA, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/611162"},{"mim_id":"607948","title":"MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/607948"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Cytokinetic bridge","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":59.2}],"url":"https://www.proteinatlas.org/search/CISH"},"hgnc":{"alias_symbol":["CIS","G18","CIS-1","SOCS"],"prev_symbol":[]},"alphafold":{"accession":"Q9NSE2","domains":[{"cath_id":"3.30.505.10","chopping":"61-170_205-217","consensus_level":"medium","plddt":87.6965,"start":61,"end":217},{"cath_id":"1.10.750.20","chopping":"221-258","consensus_level":"medium","plddt":91.5392,"start":221,"end":258}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NSE2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NSE2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NSE2-F1-predicted_aligned_error_v6.png","plddt_mean":72.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CISH","jax_strain_url":"https://www.jax.org/strain/search?query=CISH"},"sequence":{"accession":"Q9NSE2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NSE2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NSE2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NSE2"}},"corpus_meta":[{"pmid":"17525754","id":"PMC_17525754","title":"SOCS proteins, cytokine signalling and immune regulation.","date":"2007","source":"Nature reviews. 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degradation, thereby impairing phagosomal acidification in macrophages infected with Mycobacterium tuberculosis. M. tuberculosis infection induces GM-CSF secretion, which drives STAT5-mediated CISH expression, and CISH silencing reduces M. tuberculosis replication in macrophages.\",\n      \"method\": \"Loss-of-function (CISH silencing), proteasome inhibitor assay, intracellular bacterial replication assay, identification of V-ATPase subunit A as CISH substrate\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional validation with CISH knockdown, identified molecular substrate (ATP6V1A), mechanistic pathway from GM-CSF→STAT5→CISH→V-ATPase degradation established with multiple methods\",\n      \"pmids\": [\"28954234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CISH targets ATP6V1A, an essential component of the proton pump V-ATPase, for proteasomal degradation in activated T cells, thereby impairing lysosomal function, causing intracellular accumulation of multivesicular bodies and amphisomes, and promoting release of mitochondrial DNA (mtDNA) into the extracellular environment contributing to inflammaging. CISH expression is elevated in T cells from older adults, and CISH silencing restores lysosomal activity and prevents amphisomal mtDNA release.\",\n      \"method\": \"CISH silencing in human T cells, lysosomal activity assays, multivesicular body/amphisome imaging, mtDNA release quantification, in vivo antigen-specific CD4+ T cell experiments in CISH-deficient mice\",\n      \"journal\": \"Nature aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, KO, live imaging, functional assays) in both human cells and mouse models, identifies ATP6V1A as substrate, links CISH-mediated V-ATPase degradation to a defined cellular phenotype\",\n      \"pmids\": [\"37118554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CISH is induced during dendritic cell (DC) development from bone marrow progenitors and negatively regulates STAT5 activation at later stages of DC development, thereby shutting down DC progenitor proliferation and facilitating DC differentiation. CISH knockdown reduced MHC class I, co-stimulatory molecules, and pro-inflammatory cytokine expression in BMDCs but enhanced DC yield. CISH expression was required for DC-mediated CTL activation and DC-based tumor immunotherapy.\",\n      \"method\": \"CISH knockdown in mouse BMDCs, cell cycle and apoptosis analysis, STAT5 phosphorylation assays, OT-1/OT-2 T cell co-culture proliferation assays, DC-based tumor immunotherapy model\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotypes and mechanistic link to STAT5 negative feedback, single lab\",\n      \"pmids\": [\"22002016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CISH protein acts as a direct target of miR-944 in oral squamous cell carcinoma cells; CISH modulates STAT3 activity, and miR-944-induced STAT3 phosphorylation, pro-inflammatory cytokine secretion, migration, and invasion were abolished by CISH restoration, demonstrating that CISH negatively regulates STAT3 signaling.\",\n      \"method\": \"Luciferase reporter assay confirming miR-944 targeting of CISH 3'UTR, gain- and loss-of-function experiments, STAT3 phosphorylation assays, transwell migration/invasion assays, ELISA for cytokines\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct target validation by luciferase assay, rescue experiments with CISH restoration, multiple functional readouts; single lab\",\n      \"pmids\": [\"32961483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CIS (CISH) is induced by IL-6 (via STAT3) in the liver and, together with SOCS-3, inhibits growth hormone (GH)-induced STAT5 activation; IL-6 null mice fail to upregulate Cis and Socs-3 after LPS treatment and maintain GH-induced STAT5 activation, demonstrating that CIS mediates IL-6-dependent GH resistance.\",\n      \"method\": \"IL-6 null mice, TNFR1 null mice, immunoblots for STAT5/STAT3/GHR/Socs proteins, EMSA, real-time RT-PCR, ELISA\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis using IL-6 KO mice, multiple biochemical readouts; single lab but orthogonal methods\",\n      \"pmids\": [\"12519742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The SOCS box of CIS (CISH) can function as a modulator of substrate binding, distinguishing CIS mechanistically from other SOCS family members whose SOCS box acts primarily as an E3 ligase adaptor.\",\n      \"method\": \"Biochemical and structural domain analysis, review of functional mutagenesis data\",\n      \"journal\": \"Cytokine & growth factor reviews\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic inference from domain analysis and prior mutagenesis data; review compilation without primary experiments in this paper\",\n      \"pmids\": [\"18948053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CISH promoter polymorphisms (rs414171 and rs809451) affect CISH transcriptional activity and mRNA levels; the rs414171TT genotype associates with reduced CISH expression and altered IL-12p40 and IL-10 production in PBMCs, implicating CISH promoter variation in regulation of cytokine responses during tuberculosis.\",\n      \"method\": \"Luciferase reporter assay comparing CISH promoter haplotypes, qRT-PCR of CISH mRNA in PBMCs with different genotypes, cytokine ELISA\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct luciferase reporter assay for promoter activity, mRNA quantification, and cytokine measurement linked to specific genotypes; single lab\",\n      \"pmids\": [\"24632804\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CISH (cytokine-inducible SH2-containing protein) is an SH2 domain-containing negative regulator of JAK/STAT signaling that is transcriptionally induced by cytokines (including GM-CSF via STAT5) and acts by targeting specific substrates—most clearly the V-ATPase catalytic subunit A (ATP6V1A)—for ubiquitination and proteasomal degradation via its SOCS box, thereby impairing lysosomal/phagosomal acidification in macrophages and T cells, inhibiting STAT5 signaling in dendritic cells, and modulating STAT3 activity in epithelial and immune cells.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"CIS (cytokine-inducible SH2-containing protein / CISH) was identified as a novel cytokine-inducible immediate-early gene encoding a 257-amino acid SH2-domain-containing protein that stably associates with the tyrosine-phosphorylated beta chain of the IL-3 receptor and the tyrosine-phosphorylated EPO receptor, and forced expression of CIS reduced growth rate of hematopoietic cell lines, demonstrating a negative regulatory role in cytokine signal transduction.\",\n      \"method\": \"Co-immunoprecipitation, steroid-inducible expression system in IL-3-dependent hematopoietic cell lines, proliferation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding demonstrated with multiple receptor targets, functional readout via growth inhibition, foundational discovery paper with >630 citations\",\n      \"pmids\": [\"7796808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CIS associates with the second tyrosine residue (Tyr401) of the intracellular domain of the erythropoietin receptor. CIS exists in two forms (32 kDa and 37 kDa); the 37-kDa form is ubiquitinated and rapidly degraded by the proteasome. Proteasome inhibitors caused accumulation of ubiquitinated CIS and CIS-EPO receptor complexes, and also prolonged EPO receptor and STAT5 phosphorylation, implicating ubiquitinated CIS in proteasome-mediated inactivation of EPO receptor signaling.\",\n      \"method\": \"Co-immunoprecipitation, anti-ubiquitin immunoblotting, proteasome inhibitor treatment (ALLN, lactacystin), Western blot of receptor/STAT5 phosphorylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods, ubiquitination directly demonstrated, functional consequence of proteasome inhibition shown\",\n      \"pmids\": [\"9774439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CIS associates with the IL-2 receptor beta chain (IL-2Rbeta) via the A region (residues 313–382), inhibiting Lck-mediated phosphorylation of IL-2Rbeta and IL-2-mediated STAT5 activation. A dominant-negative CIS mutant with an altered SH2 domain confirmed that the phosphotyrosine-binding capability of the SH2 domain is essential for CIS inhibitory function.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, transfection with wild-type and SH2 mutant CIS, STAT5 activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, mutagenesis of SH2 domain to generate dominant negative, multiple signaling readouts\",\n      \"pmids\": [\"10514520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CIS inhibits growth hormone (GH)-stimulated STAT5b activation and STAT5b-dependent transcription by binding to membrane-distal tyrosine residues on the GH receptor (GHR) in a tyrosine-phosphorylation-dependent manner, a mechanism distinct from SOCS-1 (direct JAK2 inhibition) and SOCS-3 (membrane-proximal GHR tyrosines). CIS binding required tyrosine-phosphorylated GHR membrane-distal sequences; SOCS-2 behaved similarly.\",\n      \"method\": \"GST-GHR fusion protein in vitro binding assays, transfection in COS cells, STAT5b reporter assays, JAK2 phosphorylation assays, GHR tyrosine mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding assays with defined GHR deletion/mutation series, multiple SOCS family members compared, functional transcriptional readout\",\n      \"pmids\": [\"10585430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CIS suppresses PRL (prolactin) signaling by associating with the PRL receptor (PRLR) and inhibiting STAT5 activation, by a mechanism downstream of and distinct from SOCS-1's inhibition of JAK2. CIS produced ~70% inhibition of PRL-stimulated beta-casein promoter activity; this inhibition required PRLR association.\",\n      \"method\": \"Co-immunoprecipitation, transfection in HEK293 cells, beta-casein promoter luciferase reporter assay, STAT5 activation assay\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP demonstrating PRLR association, functional reporter assay, comparison with other SOCS family members\",\n      \"pmids\": [\"11713228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IL-6 inhibits hepatic GH signaling by inducing upregulation of both CIS and SOCS-3 protein through STAT3 activation. In IL-6 knockout mice, LPS-induced suppression of GH-stimulated STAT5 activation was abrogated, and CIS and SOCS-3 were not induced, establishing CIS as part of the IL-6/STAT3-mediated negative feedback on GH/STAT5 signaling in the liver.\",\n      \"method\": \"IL-6 and TNFR1 knockout mouse models, LPS administration, immunoblot for STAT5/STAT3 phosphorylation and CIS/SOCS-3 protein levels, real-time RT-PCR, ELISA\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis using knockout mice, multiple orthogonal methods, specific phenotypic rescue\",\n      \"pmids\": [\"12519742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The SOCS box of CIS can function as a modulator of substrate binding, representing a distinct role compared to other SOCS box functions. This places CIS as using the SOCS box not only for E3 ligase recruitment but also for altering its own substrate-binding properties.\",\n      \"method\": \"Structural/biochemical analysis reviewed with experimental data\",\n      \"journal\": \"Cytokine & growth factor reviews\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — review paper citing experimental work; the specific experimental basis for CIS SOCS box modulating substrate binding is not directly described in an included primary paper\",\n      \"pmids\": [\"18948053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RACK1 forms a complex with DLC1 and BimEL (a pro-apoptotic protein), and CIS mediates the degradation of BimEL through an ElonginB/C–Cullin2–CIS ubiquitin-protein isopeptide ligase (E3) complex upon paclitaxel treatment. An inverse correlation between CIS and BimEL levels was observed in ovarian and breast cancer cell lines and specimens.\",\n      \"method\": \"Yeast two-hybrid (identification of RACK1 partners), co-immunoprecipitation, ubiquitination assay with ElonginB/C-Cullin2-CIS complex, Western blot, in vitro and in vivo cancer cell studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct ubiquitination assay demonstrating CIS as E3 ligase adaptor for BimEL, multiple orthogonal methods including Co-IP and in vivo validation\",\n      \"pmids\": [\"18420585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CIS expression in cholangiocytes is post-transcriptionally regulated by microRNA-98 (miR-98) and let-7, which target the 3'-UTR of CIS mRNA for translational repression without mRNA degradation. LPS stimulation or Cryptosporidium parvum infection decreased miR-98 and let-7 levels, relieving CIS translational repression and increasing CIS protein. CIS in turn enhanced IκBα degradation and regulated NF-κB activation in cholangiocytes.\",\n      \"method\": \"Luciferase reporter assay with CIS 3'-UTR, miRNA overexpression/knockdown, CIS siRNA and overexpression, NF-κB activation assays, Western blot\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'-UTR targeting demonstrated by luciferase assay and miRNA manipulation, functional consequence on NF-κB shown by gain- and loss-of-function\",\n      \"pmids\": [\"19592657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CISH polymorphisms in the promoter region are associated with susceptibility to bacteremia, tuberculosis, and severe malaria. The -292 variant reduced CISH expression by 25–40% in peripheral blood mononuclear cells stimulated to produce IL-2, demonstrating that CISH controls interleukin-2 signaling and that its expression level determines host resistance to infectious diseases.\",\n      \"method\": \"Case-control association study, functional PBMC stimulation assays measuring CISH mRNA levels by genotype\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional PBMC assay supporting promoter variant effect on CISH expression; primary genetic association; mechanism inferred from expression data\",\n      \"pmids\": [\"20484391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CISH is induced during dendritic cell (DC) development from bone marrow cells and plays a role in type 1 DC development and DC-mediated CTL activation. CISH knockdown increased DC yield (via cell-cycle activation and reduced apoptosis) but reduced MHC class I, co-stimulatory molecule expression, pro-inflammatory cytokines, and impaired CTL priming. CISH-mediated negative feedback on STAT5 activation terminates DC progenitor proliferation and promotes DC differentiation into CTL stimulators.\",\n      \"method\": \"CISH knockdown in bone marrow-derived DCs, flow cytometry, cell cycle analysis, STAT5 phosphorylation assay, T cell proliferation assay, tumor immunotherapy model\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — defined cellular phenotype with STAT5 mechanistic link, multiple functional readouts, single lab\",\n      \"pmids\": [\"22002016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CISH (CIS) associates with the IL-2 receptor complex and regulates Treg expansion induced by Mycobacterium tuberculosis. PD-1 siRNA inhibited CISH expression in expanded Tregs, placing CIS downstream of PD-1 in the M. tuberculosis-induced Treg expansion pathway. CISH siRNA and anti-PD-1 siRNA each blocked M. tuberculosis-stimulated Treg expansion from CD4+CCR4+ cells.\",\n      \"method\": \"siRNA knockdown of PD-1 and CISH, flow cytometry for Treg expansion, cytokine measurement (TGF-β, IL-10, IFN-γ)\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — siRNA functional data with defined cellular phenotype; pathway placement by epistasis (PD-1 upstream of CISH)\",\n      \"pmids\": [\"21383382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"M. tuberculosis infection of macrophages induces GM-CSF secretion, which triggers STAT5-mediated expression of CISH; CISH then selectively targets the V-ATPase catalytic subunit A (ATP6V1A) for ubiquitination and proteasomal degradation, impairing phagosomal acidification and promoting mycobacterial survival. Inhibition of CISH expression reduced M. tuberculosis replication in macrophages.\",\n      \"method\": \"Macrophage infection models, CISH knockdown/inhibition, ubiquitination assay, V-ATPase subunit localization and abundance assays, bacterial replication assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct ubiquitination of ATP6V1A by CISH demonstrated, functional consequence (phagosomal acidification, bacterial replication) confirmed by loss-of-function\",\n      \"pmids\": [\"28954234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CIS (CISH) negatively regulates GM-CSF receptor signaling in NK cells. CIS-deficient NK cells displayed enhanced GM-CSF-driven signaling, and CISH deletion in NK cells exacerbated autoantibody-mediated inflammatory arthritis and experimental allergic encephalomyelitis, demonstrating that endogenous CIS provides a key brake on GM-CSF receptor-mediated NK cell activation.\",\n      \"method\": \"CIS knockout mouse models, GM-CSF fate reporter mice, cytokine production assays, NK cell-specific GM-CSF deletion, disease models (arthritis, EAE)\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with specific receptor signaling pathway (GM-CSFR), multiple in vivo disease models, cell-specific deletion\",\n      \"pmids\": [\"32097462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CISH expression is elevated in T cells from older adults and impairs lysosomal function by targeting ATP6V1A (V-ATPase proton pump catalytic subunit) for proteasomal degradation. Impaired lysosomal activity leads to accumulation of multivesicular bodies and amphisomes and export of mitochondrial DNA (mtDNA) into the environment, contributing to inflammaging. CISH silencing in T cells from older adults restored lysosomal activity and prevented amphisomal mtDNA release.\",\n      \"method\": \"CISH overexpression and siRNA knockdown in T cells, lysosomal activity assays, V-ATPase subunit abundance measurement, multivesicular body/amphisome imaging, mtDNA release assay, in vivo antigen-specific response in CISH-deficient CD4+ T cells\",\n      \"journal\": \"Nature aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway (CISH → ATP6V1A degradation → lysosomal failure → amphisomal mtDNA release) validated by multiple orthogonal methods and in vivo confirmation\",\n      \"pmids\": [\"37118554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-944 directly targets CISH mRNA, downregulating CISH protein in oral squamous cell carcinoma (OSCC). Loss of CISH leads to increased STAT3 phosphorylation, pro-inflammatory cytokine secretion, and enhanced cell migration and invasion; restoration of CISH abolished these oncogenic effects of miR-944, placing CISH as a direct post-transcriptional target of miR-944 that modulates STAT3 activity.\",\n      \"method\": \"Luciferase reporter assay (3'-UTR targeting), qRT-PCR, immunohistochemistry, gain- and loss-of-function (miR-944 and CISH), transwell migration/invasion assay, ELISA for cytokines\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'-UTR targeting validated by luciferase assay, rescue experiment showing CISH-dependent phenotype, multiple functional readouts\",\n      \"pmids\": [\"32961483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CISH promoter polymorphisms (rs414171 and rs809451) alter CISH transcriptional activity; the G(-809451)-A(-414171)-C(-622502) haplotype drove 5.43-fold higher reporter expression compared to the risk haplotype. PBMCs carrying rs414171TT showed reduced CISH mRNA and increased IL-12p40 and IL-10 production, demonstrating that CISH promoter variants functionally regulate CISH expression and downstream cytokine responses in the context of TB susceptibility.\",\n      \"method\": \"Luciferase reporter assay (promoter variants), qRT-PCR of CISH mRNA in PBMCs, ELISA for IL-12p40 and IL-10, case-control genotyping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — promoter function demonstrated by reporter assay, cytokine consequence measured; primarily genetic association study with functional follow-up\",\n      \"pmids\": [\"24632804\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CISH (CIS) is a cytokine-inducible SH2-domain-containing protein that functions as a negative feedback inhibitor of cytokine signaling by: (1) binding tyrosine-phosphorylated cytokine receptors (IL-2Rβ, EPO-R, GHR, PRLR, GM-CSFR) via its SH2 domain to block STAT5 activation; (2) acting as a substrate-recognition adaptor for an ElonginB/C–Cullin2–CISH E3 ubiquitin ligase complex to target specific substrates (BimEL, ATP6V1A/V-ATPase subunit A) for proteasomal degradation; (3) being itself rapidly ubiquitinated and proteasomally degraded to limit its own accumulation; and (4) having its expression post-transcriptionally regulated by miR-98, let-7, and miR-944, while its transcription is driven by STAT5 in response to IL-2 and GM-CSF stimulation, creating a classic negative feedback loop.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CISH (cytokine-inducible SH2-containing protein) is a SOCS-family negative feedback regulator of JAK/STAT signaling that is transcriptionally induced by cytokines—including GM-CSF via STAT5 and IL-6 via STAT3—and functions to attenuate STAT5 and STAT3 activation in immune and epithelial cells [PMID:12519742, PMID:22002016, PMID:32961483]. Its principal characterized substrate is the V-ATPase catalytic subunit ATP6V1A, which CISH targets for ubiquitination and proteasomal degradation via its SOCS box, thereby impairing phagosomal and lysosomal acidification; this mechanism promotes intracellular Mycobacterium tuberculosis survival in macrophages and drives age-related lysosomal dysfunction, amphisome accumulation, and mitochondrial DNA release in T cells [PMID:28954234, PMID:37118554]. In dendritic cells, CISH negatively regulates STAT5 to limit progenitor proliferation and promote differentiation, and is required for effective DC-mediated cytotoxic T cell priming and antitumor immunity [PMID:22002016].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that CISH is induced downstream of IL-6/STAT3 in vivo and participates in cross-inhibition of GH/STAT5 signaling answered how acute inflammation suppresses growth hormone action in the liver.\",\n      \"evidence\": \"IL-6 knockout mice failed to upregulate Cis after LPS; immunoblot, EMSA, and RT-PCR in mouse liver\",\n      \"pmids\": [\"12519742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CISH alone is sufficient for GH resistance or requires cooperation with SOCS3 was not resolved\",\n        \"No direct biochemical demonstration of CISH binding to GH receptor or JAK2\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Domain analysis proposed that the CISH SOCS box modulates substrate binding rather than acting solely as a canonical E3 ligase adaptor, distinguishing CISH mechanistically from other SOCS proteins.\",\n      \"evidence\": \"Compilation of mutagenesis and biochemical domain analysis (review)\",\n      \"pmids\": [\"18948053\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No primary structural or reconstitution data presented in this study; inference from prior mutagenesis\",\n        \"No quantitative binding or ubiquitination assays comparing SOCS box mutants\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that CISH limits STAT5 activation during DC development revealed how cytokine-induced negative feedback balances progenitor expansion with terminal differentiation and immunostimulatory capacity.\",\n      \"evidence\": \"CISH knockdown in mouse BMDCs; STAT5 phosphorylation, MHC/co-stimulatory molecule expression, OT-1/OT-2 T cell co-culture, and DC-based tumor immunotherapy\",\n      \"pmids\": [\"22002016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct CISH substrate in DCs (receptor or kinase) not identified\",\n        \"Findings from a single lab using one knockdown approach\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linking CISH promoter polymorphisms to quantitative differences in CISH mRNA and downstream cytokine output (IL-12p40, IL-10) provided a genetic mechanism for inter-individual variation in innate immune responses to tuberculosis.\",\n      \"evidence\": \"Luciferase promoter reporter assays, qRT-PCR, and ELISA in human PBMCs stratified by rs414171/rs809451 genotype\",\n      \"pmids\": [\"24632804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional intermediary between CISH level and IL-12p40/IL-10 output not defined\",\n        \"Association study without causal gene editing at the endogenous locus\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying ATP6V1A as a direct CISH ubiquitination substrate established the first defined molecular mechanism by which CISH impairs phagosomal acidification, explaining how M. tuberculosis exploits host CISH expression for intracellular survival.\",\n      \"evidence\": \"CISH silencing in macrophages, proteasome inhibitor treatment, intracellular bacterial replication assays, ATP6V1A protein level measurement\",\n      \"pmids\": [\"28954234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the CISH SH2 domain directly contacts ATP6V1A or requires adaptors was not structurally resolved\",\n        \"Relative contribution of CISH versus other SOCS members in phagosomal acidification not determined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that CISH restoration abolishes miR-944-driven STAT3 phosphorylation, migration, and invasion in oral carcinoma cells extended CISH's negative regulatory role to the STAT3 axis in epithelial cancer.\",\n      \"evidence\": \"Luciferase reporter confirming miR-944 targeting of CISH 3′UTR, gain/loss-of-function rescue, STAT3 phosphorylation, transwell assays, cytokine ELISA\",\n      \"pmids\": [\"32961483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which CISH inhibits STAT3 (direct binding vs. upstream kinase modulation) not defined\",\n        \"Single cancer cell line; generalizability unclear\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that CISH-mediated ATP6V1A degradation in aged T cells impairs lysosomal function and triggers extracellular mitochondrial DNA release connected CISH to inflammaging and provided a cell-intrinsic mechanism for age-related immune dysfunction.\",\n      \"evidence\": \"CISH silencing in human T cells, CISH-deficient mice, lysosomal activity assays, amphisome/MVB imaging, mtDNA quantification\",\n      \"pmids\": [\"37118554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CISH elevation in aged T cells is driven by specific cytokine changes or epigenetic deregulation not resolved\",\n        \"No structural characterization of the CISH–ATP6V1A interface\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for CISH's SH2 domain recognition of ATP6V1A and the full repertoire of CISH ubiquitination substrates beyond ATP6V1A remain undefined, as does the mechanistic basis by which CISH inhibits STAT3.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No co-crystal or cryo-EM structure of CISH bound to any substrate\",\n        \"Comprehensive substrate identification (e.g., ubiquitin proteomics) not performed\",\n        \"CISH's role in STAT3 regulation lacks a defined molecular target\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ATP6V1A\",\n      \"STAT5\",\n      \"STAT3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"CISH (cytokine-inducible SH2-containing protein) is a STAT5-induced negative-feedback regulator of JAK–STAT signaling that broadly restrains cytokine responses in hematopoietic and immune cells. Its SH2 domain binds tyrosine-phosphorylated cytokine receptor chains—including IL-2Rβ, EPO-R, GHR, PRLR, and GM-CSFR—to competitively block STAT5 recruitment and activation [PMID:7796808, PMID:10514520, PMID:10585430, PMID:11713228, PMID:32097462]. Beyond receptor antagonism, CISH functions as the substrate-recognition subunit of an ElonginB/C–Cullin2 E3 ubiquitin ligase complex that targets the pro-apoptotic protein BimEL and the V-ATPase catalytic subunit ATP6V1A for proteasomal degradation, thereby regulating apoptosis and phagosomal/lysosomal acidification in macrophages and T cells [PMID:18420585, PMID:28954234, PMID:37118554]. CISH itself undergoes rapid ubiquitin-dependent proteasomal turnover and is subject to post-transcriptional repression by miR-98, let-7, and miR-944, which together fine-tune the amplitude and duration of its inhibitory activity [PMID:9774439, PMID:19592657, PMID:32961483].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"The discovery of CISH as a cytokine-inducible SH2-containing protein that binds phosphorylated IL-3Rβ and EPO-R and suppresses hematopoietic cell growth established it as a new class of negative feedback regulator of cytokine signaling.\",\n      \"evidence\": \"Co-immunoprecipitation and steroid-inducible expression in IL-3-dependent cell lines with proliferation assays\",\n      \"pmids\": [\"7796808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of growth suppression unknown\", \"Receptor specificity beyond IL-3R and EPO-R uncharacterized\", \"Relationship to other SH2-domain inhibitors (SOCS family) undefined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstration that CISH is ubiquitinated and rapidly degraded by the proteasome—and that blocking proteasomal degradation prolongs EPO-R/STAT5 signaling—revealed a self-limiting regulatory circuit in which CISH's own turnover controls signaling duration.\",\n      \"evidence\": \"Anti-ubiquitin immunoblotting, proteasome inhibitor treatment (ALLN, lactacystin), phosphorylation kinetics of EPO-R and STAT5\",\n      \"pmids\": [\"9774439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase responsible for CISH ubiquitination not identified\", \"Whether CISH ubiquitination targets receptor complexes for co-degradation not resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Mapping CISH's SH2-dependent binding to IL-2Rβ and to membrane-distal phosphotyrosines on GHR, and showing that this blocks STAT5 activation without inhibiting JAK2 directly, defined a receptor-proximal competitive mechanism distinct from SOCS-1/SOCS-3.\",\n      \"evidence\": \"Co-IP with IL-2Rβ deletion mutants, SH2-domain dominant-negative mutant, GST-GHR fusion binding assays, STAT5b reporter assays\",\n      \"pmids\": [\"10514520\", \"10585430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for selective phosphotyrosine recognition not determined\", \"Stoichiometry of CISH at native receptor complexes unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Extension to the prolactin receptor showed CISH inhibits PRL/STAT5 signaling by associating with PRLR, broadening the model to include a role in lactation-related cytokine pathways.\",\n      \"evidence\": \"Co-IP in HEK293 cells, beta-casein promoter luciferase reporter\",\n      \"pmids\": [\"11713228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance for mammary gland biology not tested\", \"Binding site on PRLR not mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"IL-6/STAT3-driven induction of CISH in liver established a cross-cytokine regulatory axis in which inflammatory IL-6 signaling suppresses GH/STAT5 signaling through CISH upregulation, providing in vivo evidence from IL-6-knockout mice.\",\n      \"evidence\": \"IL-6 and TNFR1 knockout mice, LPS challenge, immunoblot for STAT5/STAT3 phosphorylation and CIS protein\",\n      \"pmids\": [\"12519742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of CISH versus SOCS-3 to GH resistance not separated genetically\", \"Tissue-specific regulation beyond liver unexplored\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of CISH as the substrate adaptor of an ElonginB/C–Cullin2 E3 ligase complex that ubiquitinates the pro-apoptotic protein BimEL established a second molecular activity for CISH beyond receptor competition—direct substrate targeting for degradation.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, in vitro ubiquitination reconstitution with ElonginB/C-Cullin2-CIS, cancer cell line and specimen correlation\",\n      \"pmids\": [\"18420585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full substrate repertoire of the Cullin2-CISH E3 ligase unknown\", \"Structural basis for BimEL recognition not determined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery that miR-98 and let-7 post-transcriptionally repress CISH by targeting its 3′-UTR, and that CISH in turn promotes IκBα degradation and NF-κB activation, revealed a previously unknown miRNA-regulated layer of CISH control and an unexpected connection to innate immune NF-κB signaling.\",\n      \"evidence\": \"Luciferase 3′-UTR reporter, miRNA overexpression/knockdown, NF-κB activation assays in cholangiocytes upon LPS and C. parvum infection\",\n      \"pmids\": [\"19592657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking CISH to IκBα degradation not elucidated\", \"Generalizability of miR-98/let-7 regulation to immune cell types not shown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"CISH's role was extended to immune cell differentiation: it terminates STAT5-driven DC progenitor proliferation and promotes type-1 DC maturation required for CTL priming, and it participates in PD-1-dependent Treg expansion during M. tuberculosis infection.\",\n      \"evidence\": \"CISH knockdown in bone-marrow-derived DCs with flow cytometry and CTL priming assays; PD-1 and CISH siRNA epistasis in M. tuberculosis-stimulated Treg expansion\",\n      \"pmids\": [\"22002016\", \"21383382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CISH is required for DC differentiation in vivo not demonstrated with conditional knockout\", \"Mechanism of PD-1-driven CISH induction in Tregs not defined biochemically\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CISH was shown to be exploited by M. tuberculosis: GM-CSF/STAT5-induced CISH targets V-ATPase subunit ATP6V1A for ubiquitin-dependent degradation, impairing phagosomal acidification and enabling intracellular bacterial survival.\",\n      \"evidence\": \"Macrophage infection, CISH knockdown/inhibition, ubiquitination assay for ATP6V1A, phagosomal acidification and bacterial replication measurements\",\n      \"pmids\": [\"28954234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ATP6V1A is a direct Cullin2-CISH E3 substrate or requires additional adaptors not fully resolved\", \"Relevance to human TB macrophages in vivo not confirmed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic deletion of CISH in NK cells revealed that CISH restrains GM-CSF receptor signaling and that its loss exacerbates autoimmune inflammation, establishing CISH as a cell-intrinsic checkpoint on NK cell activation in vivo.\",\n      \"evidence\": \"CIS-knockout and NK-cell-specific GM-CSFR-deletion mice, arthritis and EAE disease models, cytokine assays\",\n      \"pmids\": [\"32097462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise signaling intermediates downstream of GM-CSFR that CISH targets in NK cells not identified\", \"Therapeutic relevance of CISH modulation in autoimmunity not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Elevated CISH in aged T cells was linked to lysosomal failure via ATP6V1A degradation, causing amphisomal accumulation and extracellular release of mitochondrial DNA—a mechanism contributing to inflammaging—and CISH silencing rescued these defects.\",\n      \"evidence\": \"CISH overexpression/siRNA in human T cells, lysosomal activity and V-ATPase subunit assays, amphisome/mtDNA imaging, in vivo CISH-deficient CD4+ T cell responses\",\n      \"pmids\": [\"37118554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CISH-driven lysosomal dysfunction operates in non-T immune cells during aging is unknown\", \"Upstream signals driving age-dependent CISH overexpression not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A comprehensive structural model of the CISH SH2 domain in complex with phosphorylated receptor peptides and of the Cullin2–ElonginB/C–CISH E3 holoenzyme is lacking, and the full substrate repertoire of the CISH E3 ligase remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of CISH SH2 bound to any receptor phosphopeptide\", \"Complete substrate catalog of Cullin2-CISH E3 ligase not established\", \"Relative contribution of receptor-blocking versus E3-ligase activity to CISH's physiological effects not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 3, 4, 13]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [7, 12, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 10, 11, 12, 13, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 7, 12, 14]}\n    ],\n    \"complexes\": [\n      \"ElonginB/C–Cullin2–CISH E3 ubiquitin ligase\"\n    ],\n    \"partners\": [\n      \"IL2RB\",\n      \"EPOR\",\n      \"GHR\",\n      \"PRLR\",\n      \"CSF2RB\",\n      \"ATP6V1A\",\n      \"BCL2L11\",\n      \"RACK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}