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

Tara D Fischer; Eric N Bunker; Peng-Peng Zhu; François Le Guerroué; Mahan Hadjian; Eunice Dominguez-Martin; Francesco Scavone; Robert Cohen; Tingting Yao; Yan Wang; Achim Werner; Richard J Youle

doi:10.1038/s44318-024-00291-2

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

EMBO J. 2024 Nov 22. doi: 10.1038/s44318-024-00291-2. Online ahead of print.

Authors

Tara D Fischer¹, Eric N Bunker², Peng-Peng Zhu², François Le Guerroué^{2

3}, Mahan Hadjian², Eunice Dominguez-Martin², Francesco Scavone^{4

5}, Robert Cohen⁴, Tingting Yao⁴, Yan Wang⁶, Achim Werner⁷, Richard J Youle⁸

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.