2. Academic Validation
  3. Targeting LYPLAL1-mediated cGAS depalmitoylation enhances the response to anti-tumor immunotherapy

Targeting LYPLAL1-mediated cGAS depalmitoylation enhances the response to anti-tumor immunotherapy

  • Mol Cell. 2023 Oct 5;83(19):3520-3532.e7. doi: 10.1016/j.molcel.2023.09.007.
Yizeng Fan 1,  Yang Gao 1,  Li Nie 2,  Tao Hou 1,  Weichao Dan 1,  Zixi Wang 1,  Tianjie Liu 1,  Yi Wei 1,  Yuzhao Wang 1,  Bo Liu 1,  Taotao Que 1,  Yuzeshi Lei 1,  Jin Zeng 1,  Jian Ma 1,  Wenyi Wei 3,  Lei Li 4
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
  • 2 State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang 315000, P.R. China.
  • 3 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
  • 4 Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China. Electronic address: [email protected].
PMID: 37802025 DOI: 10.1016/j.molcel.2023.09.007
Abstract

Cyclic GMP-AMP Synthase (cGAS) binds pathogenic and other cytoplasmic double-stranded DNA (dsDNA) to catalyze the synthesis of cyclic GMP-AMP (cGAMP), which serves as the secondary messenger to activate the STING pathway and innate immune responses. Emerging evidence suggests that activation of the cGAS pathway is crucial for anti-tumor immunity; however, no effective intervention method targeting cGAS is currently available. Here we report that cGAS is palmitoylated by ZDHHC9 at cysteines 404/405, which promotes the dimerization and activation of cGAS. We further identified that lysophospholipase-like 1 (LYPLAL1) depalmitoylates cGAS to compromise its normal function. As such, inhibition of LYPLAL1 significantly enhances cGAS-mediated innate immune response, elevates PD-L1 expression, and enhances anti-tumor response to PD-1 blockade. Our results therefore reveal that targeting LYPLAL1-mediated cGAS depalmitoylation contributes to cGAS activation, providing a potential strategy to augment the efficacy of anti-tumor immunotherapy.

Keywords

LYPLAL1; ZDHHC9; cGAS; immunotherapy; palmitoylation.

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