2. Academic Validation
  3. Development of VHL-recruiting STING PROTACs that suppress innate immunity

Development of VHL-recruiting STING PROTACs that suppress innate immunity

  • Cell Mol Life Sci. 2023 May 14;80(6):149. doi: 10.1007/s00018-023-04796-7.
Zhichuan Zhu # 1 2,  Rebecca L Johnson # 3,  Zhigang Zhang 1 4,  Laura E Herring 5,  Guochun Jiang 2 6,  Blossom Damania 1 4 7,  Lindsey I James 8 9,  Pengda Liu 10 11
Affiliations

Affiliations

  • 1 Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 2 Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 3 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 4 Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 5 UNC Proteomics Core Facility, Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 6 UNC HIV Cure Center, Institute of Global Health and Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 7 University of North Carolina Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 8 Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. [email protected].
  • 9 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. [email protected].
  • 10 Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. [email protected].
  • 11 Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. [email protected].
  • # Contributed equally.
PMID: 37183204 DOI: 10.1007/s00018-023-04796-7
Abstract

STING acts as a cytosolic nucleotide sensor to trigger host defense upon viral or Bacterial infection. While STING hyperactivation can exert anti-tumor effects by increasing T cell filtrates, in other contexts hyperactivation of STING can contribute to autoimmune and neuroinflammatory diseases. Several STING targeting agonists and a smaller subset of antagonists have been developed, yet STING targeted degraders, or PROTACs, remain largely underexplored. Here, we report a series of STING-agonist derived PROTACs that promote STING degradation in renal cell carcinoma (RCC) cells. We show that our STING PROTACs activate STING and target activated/phospho-STING for degradation. Locking STING on the endoplasmic reticulum via site-directed mutagenesis disables STING translocation to the Proteasome and resultingly blocks STING degradation. We also demonstrate that PROTAC treatment blocks downstream innate immune signaling events and attenuates the anti-viral response. Interestingly, we find that VHL acts as a bona fide E3 ligase for STING in RCC; thus, VHL-recruiting STING PROTACs further promote VHL-dependent STING degradation. Our study reveals the design and biological assessment of VHL-recruiting agonist-derived STING PROTACs, as well as demonstrates an example of hijacking a physiological E3 ligase to enhance target protein degradation via distinct mechanisms.

Keywords

Innate immunity; PROTAC; RCC; STING; VHL.

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