2. Academic Validation
  3. LL-37 transports immunoreactive cGAMP to activate STING signaling and enhance interferon-mediated host antiviral immunity

LL-37 transports immunoreactive cGAMP to activate STING signaling and enhance interferon-mediated host antiviral immunity

  • Cell Rep. 2022 May 31;39(9):110880. doi: 10.1016/j.celrep.2022.110880.
Xubiao Wei 1,  Lulu Zhang 1,  Yinlong Yang 2,  Yanfei Hou 2,  Yifang Xu 2,  Zhimeng Wang 1,  Huili Su 2,  Fangping Han 2,  Jing Han 1,  Peiyuan Liu 3,  Shuiqing Hu 4,  Matthew D Koci 5,  Xuxu Sun 6,  Conggang Zhang 7
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Tsinghua University, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing, China.
  • 2 School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
  • 3 School of Life Science, Tianjin University, Tianjin, China.
  • 4 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 5 Prestage Department of Poultry Science, College of Agriculture and Life Sciences, North Carolina State University, Raleigh, NC, USA.
  • 6 Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University College of Basic Medical Science, Shanghai, China. Electronic address: xuxu.sun@shsmu.edu.cn.
  • 7 School of Pharmaceutical Sciences, Tsinghua University, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing, China. Electronic address: cgzhang@tsinghua.edu.cn.
PMID: 35649354 DOI: 10.1016/j.celrep.2022.110880
Abstract

Cyclic 2',3'-GMP-AMP (cGAMP) binds to and activates stimulator of interferon genes (STING), which then induces interferons to drive immune responses against tumors and pathogens. Exogenous cGAMP produced by infected and malignant cells and synthetic cGAMP used in immunotherapy must traverse the cell membrane to activate STING in target cells. However, as an anionic hydrophilic molecule, cGAMP is not inherently membrane permeable. Here, we show that LL-37, a human host defense peptide, can function as a transporter of cGAMP. LL-37 specifically binds cGAMP and efficiently delivers cGAMP into target cells. cGAMP transferred by LL-37 activates robust interferon responses and host Antiviral immunity in a STING-dependent manner. Furthermore, we report that LL-37 inducers vitamin D3 and sodium butyrate promote host immunity by enhancing endogenous LL-37 expression and its mediated cGAMP immune response. Collectively, our data uncover an essential role of LL-37 in innate immune activation and suggest new strategies for immunotherapy.

Keywords

CP: Immunology; antibacterial peptide; cGAMP; cGAS-STING signaling pathway; innate immunity; type I interferon.

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