2. Academic Validation
  3. STING induces HOIP-mediated synthesis of M1 ubiquitin chains to stimulate NF-κB signaling

STING induces HOIP-mediated synthesis of M1 ubiquitin chains to stimulate NF-κB signaling

  • EMBO J. 2025 Jan;44(1):141-165. doi: 10.1038/s44318-024-00291-2.
Tara D Fischer 1,  Eric N Bunker 2,  Peng-Peng Zhu 2,  François Le Guerroué 2 3,  Mahan Hadjian 2,  Eunice Dominguez-Martin 2,  Francesco Scavone 4 5,  Robert Cohen 4,  Tingting Yao 4,  Yan Wang 6,  Achim Werner 7,  Richard J Youle 8
Affiliations

Affiliations

  • 1 Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. fischertad@nih.gov.
  • 2 Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • 3 Single Cell Biomarkers UTechS, Institut Pasteur, Université Paris Cité, Paris, France.
  • 4 Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA.
  • 5 Department of Biology, Stanford University, Stanford, CA, USA.
  • 6 Mass Spectrometry, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
  • 7 Stem Cell Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
  • 8 Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. youler@ninds.nih.gov.
PMID: 39578541 DOI: 10.1038/s44318-024-00291-2
Abstract

STING activation by cyclic dinucleotides induces IRF3- and NF-κB-mediated gene expression in mammals, as well as lipidation of LC3B at Golgi-related membranes. While mechanisms of the IRF3 response are well understood, the mechanisms of NF-κB activation via STING remain unclear. We report here that STING activation induces linear/M1-linked ubiquitin chain (M1-Ub) formation and recruitment of the LUBAC E3 Ligase, HOIP, to LC3B-associated Golgi membranes where ubiquitin is also localized. Loss of HOIP prevents formation of M1-Ub chains and reduces STING-induced NF-κB and IRF3 signaling in human THP1 monocytes and mouse bone marrow-derived macrophages, without affecting STING activation. STING-induced LC3B lipidation is not required for M1-Ub chain formation or for immune-related gene expression, but the recently reported STING function in neutralizing Golgi pH may be involved. Thus, LUBAC synthesis of M1-linked ubiquitin chains mediates STING-induced innate immune signaling.

Keywords

Golgi; Innate Immunity; LC3B; LUBAC; NFkB.

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