Non-canonical Activation of the DNA Sensing Adaptor STING by ATM and IFI16 Mediates NF-κB Signaling after Nuclear DNA Damage.

DNA damage can be sensed as a danger-associated molecular pattern by the innate immune system. Here we find 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. This non-canonical activation of STING is mediated by the DNA binding protein IFI16, together with the DNA damage response factors ATM and PARP-1, resulting in the assembly of an alternative STING signaling complex that includes the tumor suppressor p53 and the E3 ubiquitin ligase TRAF6.

IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes.

Many human cells can sense the presence of exogenous DNA during infection though the cytosolic DNA receptor cyclic GMP-AMP synthase (cGAS), which produces the second messenger cyclic GMP-AMP (cGAMP). Other putative DNA receptors have been described, but whether their functions are redundant, tissue-specific or integrated in the cGAS-cGAMP pathway is unclear. Here we show that interferon-γ inducible protein 16 (IFI16) cooperates with cGAS during DNA sensing in human keratinocytes, as both cGAS and IFI16 are required for the full activation of an innate immune response to exogenous DNA and DNA viruses.

TRAM is required for TLR2 endosomal signaling to type I IFN induction.

Detection of microbes by TLRs on the plasma membrane leads to the induction of proinflammatory cytokines such as TNF-α, via activation of NF-κB. Alternatively, activation of endosomal TLRs leads to the induction of type I IFNs via IFN regulatory factors (IRFs). TLR4 signaling from the plasma membrane to NF-κB via the Toll/IL-1R (TIR) adaptor protein MyD88 requires the TIR sorting adaptor Mal, whereas endosomal TLR4 signaling to IRF3 via the TIR domain-containing adaptor-inducing IFN-β (TRIF) requires the TRIF-related adaptor molecule (TRAM).

The emerging role of human PYHIN proteins in innate immunity: implications for health and disease.

The innate immune response depends on the ability of immune cells to detect pathogens through germline-encoded pattern recognition receptors (PRRs). Recently discovered PRRs include some members of the Pyrin and HIN domain (PYHIN) family, which are encoded on an interferon-inducible gene cluster located on chromosome 1q23. There are five human PYHIN proteins; Absent in melanoma 2 (AIM2), IFN-γ inducible protein 16 (IFI16), Myeloid cell nuclear differentiation antigen (MNDA), Pyrin and HIN domain family member 1 (PYHIN1) and the recently identified Pyrin domain only protein 3 (POP3).

Promyelocytic leukemia protein interacts with the apoptosis-associated speck-like protein to limit inflammasome activation.

The apoptosis-associated speck-like protein containing a caspase-activating recruitment domain (ASC) is an essential component of several inflammasomes, multiprotein complexes that regulate caspase-1 activation and inflammation. We report here an interaction between promyelocytic leukemia protein (PML) and ASC. We observed enhanced formation of ASC dimers in PML-deficient macrophages.

The GOLD domain-containing protein TMED1 is involved in interleukin-33 signaling.

The proinflammatory danger signal IL-33, which is released from damaged or dying cells, achieves its effects via the IL-1R family member ST2L. The detection of IL-33 by ST2L initiates downstream signaling pathways that result in the activation of MAPKs and NF-κB. Here, we show that TMED1 associates with ST2L.

New developments in Toll-like receptor targeted therapeutics.

Toll-like receptors (TLRs) play a crucial role in host defence and inflammation. Given that a significant amount of evidence implicates TLRs in the pathogenesis of immune diseases and cancer, and their activation occurs early in the inflammatory cascade, they are attractive targets for novel therapeutic agents. Potential therapeutics include TLR-targeted antibodies, small molecules and nucleic acid based drugs.

The GOLD domain-containing protein TMED7 inhibits TLR4 signalling from the endosome upon LPS stimulation.

Toll-like receptor 4 is an innate immune receptor responsible for the recognition of the Gram-negative cell wall component lipopolysaccharide. Here we show that transmembrane emp24 domain-containing protein 7 (TMED7) inhibits MyD88-independent toll-like receptor 4 signalling. TMED7 overexpression inhibits the ability of TRAM, an adaptor utilized by toll-like receptor 4, or lipopolysaccharide to activate the interferon regulatory factor 3-signalling pathway, whereas TMED7 knockdown enhances production of the cytokine, RANTES, following lipopolysaccharide stimulation.