IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP
Kasper L Jønsson,Anders Laustsen,Christian Krapp,Christian Krapp,Kristian Alsbjerg Skipper,Karthiga Thavachelvam,Dominik Hotter,Johanne H Egedal,Mads Kjolby,Mads Kjolby,Pejman Mohammadi,Thaneas Prabakaran,Lambert K. Sørensen,Chenglong Sun,Søren B. Jensen,Christian K. Holm,Robert Jan Lebbink,Mogens Johannsen,Mette Nyegaard,Jacob Giehm Mikkelsen,Frank Kirchhoff,Søren R. Paludan,Martin R. Jakobsen +22 more
TLDR
The results suggest that IFI16 is essential for efficient sensing and signalling upon DNA challenge in macrophages to promote interferons and antiviral responses.Abstract:
Innate immune activation by macrophages is an essential part of host defence against infection. Cytosolic recognition of microbial DNA in macrophages leads to induction of interferons and cytokines through activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Other host factors, including interferon-gamma inducible factor 16 (IFI16), have been proposed to contribute to immune activation by DNA. However, their relation to the cGAS-STING pathway is not clear. Here, we show that IFI16 functions in the cGAS-STING pathway on two distinct levels. Depletion of IFI16 in macrophages impairs cGAMP production on DNA stimulation, whereas overexpression of IFI16 amplifies the function of cGAS. Furthermore, IFI16 is vital for the downstream signalling stimulated by cGAMP, facilitating recruitment and activation of TANK-binding kinase 1 in STING complex. Collectively, our results suggest that IFI16 is essential for efficient sensing and signalling upon DNA challenge in macrophages to promote interferons and antiviral responses.read more
Citations
More filters
Journal ArticleDOI
DNA sensing by the cGAS–STING pathway in health and disease
TL;DR: The cGAS–STING pathway forms a major DNA-sensing mechanism in mammalian cells and emerging evidence of its role in monogenic inflammatory diseases and cancer and new therapeutic opportunities is highlighted.
Journal ArticleDOI
Molecular mechanisms and cellular functions of cGAS–STING signalling
Karl-Peter Hopfner,Veit Hornung +1 more
TL;DR: The molecular mechanisms and cellular functions underlying cGAS–STING activation and signalling are reviewed, particularly highlighting the newly emerging diversity of this signalling pathway and discussing how the specificity towards normal, damage-induced and infection-associated DNA could be achieved.
Journal ArticleDOI
Non-canonical Activation of the DNA Sensing Adaptor STING by ATM and IFI16 Mediates NF-κB Signaling after Nuclear DNA Damage.
Gillian Dunphy,Sinead M. Flannery,Jessica F. Almine,Dympna J. Connolly,Christina Paulus,Kasper L Jønsson,Martin R. Jakobsen,Michael Nevels,Andrew G. Bowie,Leonie Unterholzner +9 more
TL;DR: It is found that keratinocytes and other human cells mount an innate immune response within hours of etoposide-induced DNA damage, which involves the DNA sensing adaptor STING but is independent of the cytosolic DNA receptor cGAS.
Journal ArticleDOI
Inflammatory microenvironment remodelling by tumour cells after radiotherapy.
Martin McLaughlin,Emmanuel C Patin,Malin Pedersen,Anna Wilkins,Magnus T. Dillon,Magnus T. Dillon,Alan Melcher,Alan Melcher,Kevin J. Harrington,Kevin J. Harrington +9 more
TL;DR: How radiotherapy, through its immunomodulating effects, represents a promising combination partner with ICIs and how DNA damage response inhibitors in combination with radiotherapy may be used to further augment this approach are described.
Journal ArticleDOI
cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein–DNA ladders
Liudmila Andreeva,Björn Hiller,Dirk Kostrewa,Charlotte Lässig,Carina C. de Oliveira Mann,Carina C. de Oliveira Mann,David Jan Drexler,Andreas Maiser,Moritz M. Gaidt,Heinrich Leonhardt,Heinrich Leonhardt,Veit Hornung,Veit Hornung,Karl-Peter Hopfner,Karl-Peter Hopfner +14 more
TL;DR: The results suggest a nucleation-cooperativity-based mechanism for sensitive detection of mitochondrial DNA and pathogen genomes, and identify HMGB/TFAM proteins as DNA-structuring host factors.
References
More filters
Journal ArticleDOI
Cyclic GMP-AMP Synthase is a Cytosolic DNA Sensor that Activates the Type-I Interferon Pathway
TL;DR: Results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP, which belongs to the nucleotidyltransferase family.
Journal ArticleDOI
IFI16 is an innate immune sensor for intracellular DNA.
Leonie Unterholzner,Sinead E. Keating,Marcin Baran,Kristy A. Horan,Søren B. Jensen,Søren B. Jensen,Shrutie Sharma,Cherilyn M. Sirois,Tengchuan Jin,Eicke Latz,Eicke Latz,T. Sam Xiao,Katherine A. Fitzgerald,Søren R. Paludan,Andrew G. Bowie +14 more
TL;DR: IFI16 (p204) is the first PYHIN protein to their knowledge shown to be involved in IFN-β induction and forms a new family of innate DNA sensors the authors call 'AIM2-like receptors' (ALRs).
Journal ArticleDOI
Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation
Siqi Liu,Xin Cai,Jiaxi Wu,Qian Cong,Xiang Chen,Tuo Li,Fenghe Du,Junyao Ren,You Tong Wu,Nick V. Grishin,Zhijian J. Chen +10 more
TL;DR: A common signaling mechanism used by all three types of innate immune receptor-adaptor protein pairs to activate IRF3 and generate IFNs is reported, which is important because cells must regulate their IFN production carefully to avoid inflammation and autoimmunity.
Journal ArticleDOI
cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING
Andrea Ablasser,Marion Goldeck,Taner Cavlar,Tobias Deimling,Gregor Witte,Ingo Röhl,Karl-Peter Hopfner,Karl-Peter Hopfner,Janos Ludwig,Veit Hornung +9 more
TL;DR: It is shown in vivo and in vitro that the cGAS-catalysed reaction product is distinct from previously characterized cyclic dinucleotides, and it is found that the presence of this 2′-5′ linkage was required to exert potent activation of human STING.
Journal ArticleDOI
STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway.
Yasuo Tanaka,Zhijian J. Chen +1 more
TL;DR: STING is shown to stimulate phosphorylation of IRF3 by the kinase TBK1 (TANK-binding kinase 1) in an in vitro reconstitution system, suggesting that STING functions as a scaffold protein to specify and promote the phosphorylated of IRf3 by TBk1.
Related Papers (5)
Cyclic GMP-AMP Synthase is a Cytosolic DNA Sensor that Activates the Type-I Interferon Pathway
STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling.
Hiroki Ishikawa,Glen N. Barber +1 more