Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Structural Studies (CSS), Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Jesko Kaiser
Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Maximilian Hirschenberger
Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
Xiao Tang
Clinic of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Haifeng C. Xu
Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Oliver Michel
Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Ronny Tao
Institute for Virology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Alexandra Haase
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
Ulrich Martin
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
Thomas Kurz
Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Ingo Drexler
Institute for Virology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Boris Görg
Clinic of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Philipp A. Lang
Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Tom Luedde
Clinic of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Konstantin M.J. Sparrer
Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
Holger Gohlke
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
Clinic of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Corresponding author
Summary: 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.
