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
  • 1. Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. [email protected].
  • 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. [email protected].
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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