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  3. Regulation of STING activity in DNA sensing by ISG15 modification

Regulation of STING activity in DNA sensing by ISG15 modification

  • Cell Rep. 2023 Oct 20;42(11):113277. doi: 10.1016/j.celrep.2023.113277.
Chaohui Lin 1,  Edmund Osei Kuffour 1,  Nina V Fuchs 2,  Christoph G W Gertzen 3,  Jesko Kaiser 4,  Maximilian Hirschenberger 5,  Xiao Tang 1,  Haifeng C Xu 6,  Oliver Michel 4,  Ronny Tao 7,  Alexandra Haase 8,  Ulrich Martin 9,  Thomas Kurz 4,  Ingo Drexler 7,  Boris Görg 1,  Philipp A Lang 6,  Tom Luedde 1,  Konstantin M J Sparrer 5,  Holger Gohlke 10,  Renate König 2,  Carsten Münk 11
Affiliations

Affiliations

  • 1 Clinic of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • 2 Host-Pathogen Interactions, Paul-Ehrlich-Institut, Langen, Germany.
  • 3 Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Structural Studies (CSS), Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • 4 Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • 5 Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
  • 6 Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • 7 Institute for Virology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • 8 Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), Hannover Medical School, 30625 Hannover, Germany; REBIRTH-Research Center for Translational and Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany.
  • 9 Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), Hannover Medical School, 30625 Hannover, Germany; REBIRTH-Research Center for Translational and Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, 30625 Hannover, Germany.
  • 10 Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, 52425 Jülich, Germany.
  • 11 Clinic of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. Electronic address: carsten.muenk@med.uni-duesseldorf.de.
PMID: 37864791 DOI: 10.1016/j.celrep.2023.113277
Abstract

Sensing of human immunodeficiency virus type 1 (HIV-1) DNA is mediated by the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling axis. Signal transduction and regulation of this cascade is achieved by post-translational modifications. Here we show that cGAS-STING-dependent HIV-1 sensing requires interferon-stimulated gene 15 (ISG15). ISG15 deficiency inhibits STING-dependent sensing of HIV-1 and STING agonist-induced Antiviral response. Upon external stimuli, STING undergoes ISGylation at residues K224, K236, K289, K347, K338, and K370. Inhibition of STING ISGylation at K289 suppresses STING-mediated type Ⅰ interferon induction by inhibiting its oligomerization. Of note, removal of STING ISGylation alleviates gain-of-function phenotype in STING-associated vasculopathy with onset in infancy (SAVI). Molecular modeling suggests that ISGylation of K289 is an important regulator of oligomerization. Taken together, our data demonstrate that ISGylation at K289 is crucial for STING activation and represents an important regulatory step in DNA sensing of viruses and autoimmune responses.

Keywords

CP: Molecular biology; DNA sensing; HIV sensing; ISG15; ISGylation; SAVI; USP18; innate immunity.

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