Leaked Mitochondrial C1QBP Inhibits Activation of the DNA Sensor cGAS

Song, Kun; Wu, Yunqin; Fu, Bishi; Wang, Lingyan; Hao, Wenzhuo; Fang, Hua; Sun, Yiwen; Dorf, Martin E.; Li, Shitao

doi:10.4049/jimmunol.2100392

Cited by 8 publications

(6 citation statements)

References 71 publications

(38 reference statements)

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“…Interestingly, histone H3 co-fractionated with cGAS in most fractions with high molecular weight (Fig. 1a ), suggesting that cGAS might associate with histones or the chromatin 15 , 27 , 29 . To further determine the subcellular localization of endogenous cGAS, we fractionated the cell lysates into five fractions: cytosol, membrane, nuclear soluble, chromatin-bound, and cytoskeletal.…”

Section: Resultsmentioning

confidence: 98%

Nuclear soluble cGAS senses double-stranded DNA virus infection

Song

Hao

et al. 2022

Commun Biol

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The DNA sensor cGAS detects cytosolic DNA and instigates type I interferon (IFN) expression. Recent studies find that cGAS also localizes in the nucleus and binds the chromatin. Despite the mechanism controlling nuclear cGAS activation is well elucidated, whether nuclear cGAS participates in DNA sensing is unclear. Here, we report that herpes simplex virus 1 (HSV-1) infection caused the release of cGAS from the chromatin into the nuclear soluble fraction. Like its cytosolic counterpart, the leaked nuclear soluble cGAS also sensed viral DNA, produced cGAMP, and induced mRNA expression of type I IFN and interferon-stimulated genes. Consistently, the nuclear soluble cGAS limited HSV-1 infection. Furthermore, enzyme-deficient mutation (D307A) or cGAS inhibitor RU.251 abolished nuclear cGAS-mediated innate immune responses, suggesting that enzymatic activity is also required for nuclear soluble cGAS. Taken all together, our study demonstrates that nuclear soluble cGAS acts as a nuclear DNA sensor detecting nuclear-replicating DNA viruses.

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Section: Resultsmentioning

confidence: 98%

Nuclear soluble cGAS senses double-stranded DNA virus infection

Song

Hao

et al. 2022

Commun Biol

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“…p32 is a toroidal (doughnut-shaped) protein that exhibits a high degree of evolutionary conservation across eukaryotes. It is primarily found within the mitochondria, representing its canonical subcellular localization 35 . On this basis, we carried out proteomics analysis to identify p32 binding proteins in the mitochondria.…”

Section: Resultsmentioning

confidence: 99%

p32 regulates glycometabolism and TCA cycle to inhibit ccRCC progression via copper-induced DLAT lipoylation oligomerization

Tian,

Wang,

Wang

et al. 2024

Int. J. Biol. Sci.

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A key player in mitochondrial respiration, p32, often referred to as C1QBP, is mostly found in the mitochondrial matrix. Previously, we showed that p32 interacts with DLAT in the mitochondria. Here, we found that p32 expression was reduced in ccRCC and suppressed progression and metastasis in ccRCC animal models. We observed that increasing p32 expression led to an increase in oxidative phosphorylation by interacting with DLAT, thus, regulating the activation of the pyruvate dehydrogenase complex (PDHc). Mechanistically, reduced p32 expression, in concert with DLAT, suppresses PDHc activity and the TCA cycle. Furthermore, our research discovered that p32 has a direct binding affinity for copper, facilitating the copper-induced oligomerization of lipo-DLAT specifically in ccRCC cells. This finding reveals an innovative function of the p32/DLAT/copper complex in regulating glycometabolism and the TCA cycle in ccRCC. Importantly, our research provides important new understandings of the underlying molecular processes causing the abnormal mitochondrial metabolism linked to this cancer.

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“…Based on knockout mouse macrophage cells, the deficiency of C1QBP protein increases the DNA sensor cyclic GMP-AMP (cGAMP) synthase-induced innate immune response 40 . Here, we observed the downregulation of C1QBP transcription associated with the upregulation of genes belonging to innate immune response (Fig.…”

Section: Resultsmentioning

confidence: 99%

Host genetic factors related to innate immunity, environmental sensing and cellular functions are associated with human skin microbiota

Moitinho‐Silva

Degenhardt²,

Rodríguez³

et al. 2022

Nat Commun

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Despite the increasing knowledge about factors shaping the human microbiome, the host genetic factors that modulate the skin-microbiome interactions are still largely understudied. This contrasts with recent efforts to characterize host genes that influence the gut microbiota. Here, we investigated the effect of genetics on skin microbiota across three different skin microenvironments through meta-analyses of genome-wide association studies (GWAS) of two population-based German cohorts. We identified 23 genome-wide significant loci harboring 30 candidate genes involved in innate immune signaling, environmental sensing, cell differentiation, proliferation and fibroblast activity. However, no locus passed the strict threshold for study-wide significance (P < 6.3 × 10−10 for 80 features included in the analysis). Mendelian randomization (MR) analysis indicated the influence of staphylococci on eczema/dermatitis and suggested modulating effects of the microbiota on other skin diseases. Finally, transcriptional profiles of keratinocytes significantly changed after in vitro co-culturing with Staphylococcus epidermidis, chosen as a representative of skin commensals. Seven candidate genes from the GWAS were found overlapping with differential expression in the co-culturing experiments, warranting further research of the skin commensal and host genetic makeup interaction.

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Leaked Mitochondrial C1QBP Inhibits Activation of the DNA Sensor cGAS

Cited by 8 publications

References 71 publications

Nuclear soluble cGAS senses double-stranded DNA virus infection

Nuclear soluble cGAS senses double-stranded DNA virus infection

p32 regulates glycometabolism and TCA cycle to inhibit ccRCC progression via copper-induced DLAT lipoylation oligomerization

Host genetic factors related to innate immunity, environmental sensing and cellular functions are associated with human skin microbiota

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