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

Xiaofeng Liao (), Wenxue Li, Hongyue Zhou, Barani Kumar Rajendran, Ao Li, Jingjing Ren, Yi Luan, David A. Calderwood, Benjamin Turk, Wenwen Tang (), Yansheng Liu () and Dianqing Wu ()
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Xiaofeng Liao: Yale University School of Medicine
Wenxue Li: Yale University School of Medicine
Hongyue Zhou: Yale University School of Medicine
Barani Kumar Rajendran: Yale University School of Medicine
Ao Li: Yale University School of Medicine
Jingjing Ren: Yale University School of Medicine
Yi Luan: Yale University School of Medicine
David A. Calderwood: Yale University School of Medicine
Benjamin Turk: Yale University School of Medicine
Wenwen Tang: Yale University School of Medicine
Yansheng Liu: Yale University School of Medicine
Dianqing Wu: Yale University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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 TCR and IL2 signaling. Additionally, CTLA4 is markedly upregulated by CUL5 knockout, and its inactivation further enhances the anti-tumor effect of CUL5 KO. These results together reveal a negative regulatory mechanism for CD8+ T cells and have strong translational implications in cancer immunotherapy.

Date: 2024
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DOI: 10.1038/s41467-024-44885-0

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