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CRISPR-Cas9 Screening Identifies UBE3C as a Top Negative Regulator of THEMIS Protein Expression

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE322555 | GEO | 2026/04/30

REPOSITORIES: GEO

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Next Generation Sequencing analysis of IL-2 induced OT-I wild-type and OT-I Themis cKO cells for three days.

Project description:Thymocyte-expressed molecule involved in selection (Themis) was identified as a T cell-specific protein for T cell development. Recently, Themis was found to be required for T cell homeostasis by orchestrating TCR signaling and cytokine, especially γc family cytokine IL-7 signaling in peraphrial CD8+ T cells. Here, our study identifies Themis as a regulator for another γc family cytokine IL-2-induced proliferation. Transcriptomics and metabolomics reveal that Themis regulates Jak-Stat, Akt-mTOR as well as the downstream metabolic pathways. Moreover, how Themis regulates Shp1 phosphatase activity is still controversial. We further demonstrate that Themis negatively regulates Shp1 phosphatase activity on Jak1 and Jak3 to facilitate downstream signaling and subsequently metabolic reprograming, highlighting the importance of Themis in metabolic responses of CD8+ T cells.

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A Themis:SHP complex promotes T cell survival

Project description:THEMIS is critical for conventional T cell development but its precise molecular function remains elusive. Here we show that THEMIS constitutively associates with the phosphatases SHP-1 and SHP-2. This complex requires the adapter GRB2, which bridges SHP to Themis in a Tyr-phosphorylation-independent fashion. Rather, SHP1 and THEMIS engage with the N-SH3 and C-SH3 domains of GRB2, respectively, a configuration that allows GRB2-SH2 to recruit the complex onto LAT. Coherent with THEMIS-mediated recruitment of SHP to the TCR signalosome, THEMIS knockdown increased TCR-induced TCR- phosphorylation, Erk activation and CD69 expression, however not Lck phosphorylation. This generalized TCR signalling increase led to augmented apoptosis, a phenotype mirrored by SHP-1 knockdown. Remarkably, a KI mutation of Lck Ser59, previously suggested to be key in ERK-mediated resistance towards SHP-1 negative feedback, did not affect TCR signalling nor ligand discrimination in vivo. Thus, THEMIS:SHP complex dampens early TCR signalling by a previously unknown molecular mechanism that favors T cell survival. We discuss possible implications of this mechanism in modulating TCR output signals towards conventional T cell development and differentiation.

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Project description:Determine the biochemical cause of impaired development of Themis-deficient thymocytes.

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