The CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8⁺ T cells.

ABSTRACT: CD8⁺ T cells play an important role in anti-tumor immunity. Better understanding of their regulation could advance cancer immunotherapies. Here we identify, via stepwise CRISPR-based screening, that CUL5 is a negative regulator of the core signaling pathways of CD8⁺ T cells. Knocking out CUL5 in mouse CD8⁺ T cells significantly improves their tumor growth inhibiting ability, with significant proteomic alterations that broadly enhance TCR and cytokine signaling and their effector functions. Chemical inhibition of neddylation required by CUL5 activation, also enhances CD8 effector activities with CUL5 validated as a major target. Mechanistically, CUL5, which is upregulated by TCR stimulation, interacts with the SOCS-box-containing protein PCMTD2 and inhibits

SUBMITTER: Liao X 

PROVIDER: S-EPMC10798966 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature