DYRK1A enhances antitumor immunity in type 1 conventional dendritic cells via mTORC1 activation
Hongjiao Wang, He Jiang, Songlin He, Songwen Ren, Haiwen Li, Wangnan Liu, Chunyun Zhou, Pan Zhu, Keren Chen, Weijia Cao, Yan Qin, Dan Du, Nengming Xiao, Hongling Huang, Chun-Jung Ko, Yiming Zheng, Bo Wang, Qiang Zou, Jian-Hong Shi, Xun Li, Zuliang Jie
Hongjiao Wang, He Jiang, Songlin He, Songwen Ren, Haiwen Li, Wangnan Liu, Chunyun Zhou, Pan Zhu, Keren Chen, Weijia Cao, Yan Qin, Dan Du, Nengming Xiao, Hongling Huang, Chun-Jung Ko, Yiming Zheng, Bo Wang, Qiang Zou, Jian-Hong Shi, Xun Li, Zuliang Jie
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Research Article Cell biology Immunology

DYRK1A enhances antitumor immunity in type 1 conventional dendritic cells via mTORC1 activation

Abstract

Type 1 conventional dendritic cells (cDC1s) play an integral role in mediating immune responses and maintaining homeostasis, yet the molecular mechanisms underlying their functions remain poorly understood. In this study, we identified dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as a key kinase that responded to TLR and growth factor stimulation and acted as an essential regulator of cDC1 function. Genetic ablation of Dyrk1a specifically in cDC1s impaired antitumor immunity and accelerated tumor progression in murine models. Mechanistically, DYRK1A mediated the phosphorylation of the mTOR complex 1 (mTORC1) inhibitor TSC2 at serine 540, triggering the degradation of TSC2 and promoting mTORC1 signaling in cDC1s. Notably, Tsc2 deletion in Dyrk1a-deficient cDC1s remarkably restored their antitumor immune functions. Furthermore, DYRK1A-mediated mTORC1 signaling in cDC1s positively correlated with effector T cell responses across multiple human cancers. Our findings highlight a critical role for the DYRK1A/TSC2/mTORC1 signaling pathway in regulating cDC1 functions in antitumor immunity, offering potential strategies to improve cancer immunotherapy.

Authors

Hongjiao Wang, He Jiang, Songlin He, Songwen Ren, Haiwen Li, Wangnan Liu, Chunyun Zhou, Pan Zhu, Keren Chen, Weijia Cao, Yan Qin, Dan Du, Nengming Xiao, Hongling Huang, Chun-Jung Ko, Yiming Zheng, Bo Wang, Qiang Zou, Jian-Hong Shi, Xun Li, Zuliang Jie

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Figure 7

DYRK1A facilitates TSC2 degradation through the phosphorylation of TSC2 at S540.

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DYRK1A facilitates TSC2 degradation through the phosphorylation of TSC2 ...
(A) Co-IP analysis of TSC2 followed by immunoblot analysis of p-Ser/Thr and indicated proteins using whole-cell lysates of HEK293 cells transfected with the indicated expression vectors. (B) Mass spectrometric analysis of potential phosphorylation sites of TSC2 by DYRK1A. (C) The panel depicts the phosphorylation site S540 in TSC2. Asterisk at the top, serine 540 residue that was found phosphorylated, determined by mass spectrometric analysis. (D) Schematic summary of conserved phosphorylation domains of DYRK1A. (E) Amino acid sequences around the serine 540 residue in TSC2 across different species. Asterisk at the top, serine residue that is conserved across species. (F) HEK293 cells were transfected with HA-DYRK1A and Flag-WT TSC2 or S540A mutant. Proteins precipitated by anti-Flag were blotted with anti–p-Ser/Thr followed by anti-TSC2. (G–I) Immunoblot analysis of TSC2 using whole-cell lysates of HEK293 cells transfected with WT TSC2 (G), S540A (H), S540D (H), and DYRK1A at the indicated time points after CHX treatment with or without MG-132. (I) Summary graph of quantified TSC2 protein bands of H (N = 4/group). Note that we transfected an excessive amount of cDNA for the S540D mutant, such that its initial expression level is close to that of the S540A mutant, to ease a direct comparison. (J) Effect of WT and mutant TSC2 on DYRK1A-induced S6K/S6/4EBP1 phosphorylation. Immunoblot analysis was performed on whole-cell lysates of HEK293 cells 48 hours after transfection with the indicated expression vectors to detect the specified proteins. Data are representative of 3 independent experiments. P values were determined using a 2-tailed unpaired Student’s t test (I). **P < 0.01; ***P < 0.001.