Cutting Edge: Novel Tmem173 Allele Reveals Importance of STING N Terminus in Trafficking and Type I IFN Production

Abstract

With the STING C-terminus being extensively studied, the role of the N-terminal domain (NTD) of STING remains an important subject of investigation. Here we identify novel mutations in NTD of Sting of the MOLF strain in response to Herpes Simplex Virus and Listeria monocytogenes both in vitro and in vivo. These mutations are responsible for low levels of IFNβ due to failure of MOLF STING to translocate from the ER. These data provide the first evidence that the NTD of STING affects DNA-responses via control of trafficking. They also show that the genetic diversity of wild-derived mice resembles the diversity observed in humans. Several human alleles of STING confer attenuated IFN-I production similar to what we observe with the MOLF Sting allele, a crucial functional difference not apparent in classical inbred mice. Thus, understanding the functional significance of polymorphisms in MOLF STING can provide basic mechanistic insights relevant to humans.

Tofacitinib relieves symptoms of stimulator of interferon genes (STING)–associated vasculopathy with onset in infancy caused by 2 de novo variants in TMEM173

“…In line with the current conception, we have recently reported a 40% reduction in AD among 2-year-old children with maternal probiotic supplementation from the Prevention of Allergy among Children in Trondheim (ProPACT) cohort, 4 which is a randomized double-blind placebo-controlled study. Despite the major effect on AD, there was little or no effect of the probiotic on the gut microbiota composition through the first 2 years of life.…”

“…Analysis of Ser102 was unavailable, although a recent study suggests that Ser103 is important for maintaining proper subcellular localization. 4 Based on the known functions of STING, we investigated further the functional consequences of the STING variants. First, patient-derived fibroblasts displayed increased expression of IFN-b, helping to explain the increased inflammatory responses in the patient (Fig 2, A).…”

“…ProPACT, a randomized double-blind intervention study, was started in 2003 and is described in detail in Dotterud et al 4 In short, women received daily doses of probiotic-containing fermented milk starting from 36th gestation week until 3 months after birth.…”

When STING Meets Viruses: Sensing, Trafficking and Response

“…Human STING encodes a protein of 379 amino acids (aa), containing a predicted transmembrane portion (1-173aa) in the N-terminus and an intracellular soluble portion (174-379aa) in the C-terminus ( 64 ). The N-terminus regulates its cellular localization and homodimerization, since the transmembrane domains cross the ER membrane ( 61 , 65 ). The C-terminal domain (CTD) functionally docks downstream molecules, including TBK1/IKKε, and IRF3/IRF7 ( 66 – 68 ).…”

Constitutive Interferon Attenuates RIPK1/3-Mediated Cytokine Translation

“…We have termed this MOLF-specific increase in cytokine and chemokine production upon LZ treatment ''RIPK-kinase-dependent inflammation'' or the ''RIPK-kinase-dependent inflammatory phenotype.'' MOLF BMDMs are resistant to LZ-induced necroptosis compared with B6 ( Figure 1C), because of a hypomorphic allele of Sting (stimulator of IFN genes), which regulates MLKL, an important effector of necroptosis, as well as a number of other ISGs (Surpris et al, 2015;Sarhan et al, 2018). Although total MLKL levels were reduced in MOLF macrophages, MLKL phosphorylation and upstream RIPK1 phosphorylation were uninhibited, indicating that RIPK1 kinase activity was functional in MOLF macrophages ( Figure 1D) (Sarhan et al, 2018).…”