{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE322nnn/GSE322555/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Other"],"species":["Homo sapiens"],"gds_type":["Other"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE322555"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"CRISPR-Cas9 Screening Identifies UBE3C as a Top Negative Regulator of THEMIS Protein Expression","description":"THEMIS is an essential T-cell receptor signal modulator critical for T-cell development and peripheral homeostasis; however, the machinery governing its protein stability remains elusive. Utilizing unbiased CRISPR/Cas9 screening integrated with affinity purification-mass spectrometry, we identify UBE3C as the physiological E3 ligase for THEMIS. Mechanistically, UBE3C interacts with the CABIT1 domain of THEMIS and catalyzes K48-linked polyubiquitination, primarily targeting the conserved Lysine 208 residue for proteasomal degradation. UBE3C deletion in T cells in vivo results in normal thymic T cell development but causes an age-dependent defect in peripheral T cell homeostasis. Most critically, genetic epistasis analysis demonstrates that UBE3C deletion alleviates the developmental block in Themis+/- mice and rescues the peripheral homeostatic defects of UBE3C-deficient mice. Our findings establish the UBE3C-THEMIS axis as the core ubiquitin-dependent protein quality control module, revealing an unrecognized role for UBE3C in adaptive immunity and providing a molecular explanation for the exquisite dosage sensitivity of THEMIS.","dates":{"publication":"2026/04/30"},"accession":"GSE322555","cross_references":{"GSM":["GSM9554213","GSM9554214","GSM9554215","GSM9554216","GSM9554217","GSM9554218"],"GPL":["21697"],"GSE":["322555"],"taxon":["Homo sapiens"]}}