A non-canonical cGAS–STING–PERK pathway facilitates the translational program critical for senescence and organ fibrosis

Zhang, Dan; Liu, Yutong; Zhu, Yezhang; Zhang, Qian; Guan, Hongxing; Liu, Shengduo; Chen, Shasha; Chen, Mei; Chen, Chen; Liao, Zhiyong; Xi, Ying; Ouyang, Songying; Feng, Xin‐Hua; Liang, Tingbo; Shen, Li; Xu, Pinglong

doi:10.1038/s41556-022-00894-z

Cited by 130 publications

(98 citation statements)

References 111 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, in 433 kidney tissue samples from patients with CKD, CGAS and STING1 expression correlated positively with the degree of kidney fibrosis 7 . Although these studies did not interrogate the downstream signalling cascade, cGAS–STING activation was shown to mediate kidney fibrosis through a non-canonical pathway (that is, independently of the cGAS–STING–TBK1–IRF3 pathway) 115 . In the unilateral ureteral obstruction model of kidney fibrosis, upon binding to cGAMP, STING was shown to interact directly with PKR-like ER kinase (PERK), which triggered phosphorylation of eukaryotic initiation factor 2α (eIF2α) and led to increased collagen expression and kidney fibrosis by modulating damage-initiated mRNA translation 115 .…”

Section: Cgas–sting In Diseasementioning

confidence: 98%

“…Although these studies did not interrogate the downstream signalling cascade, cGAS–STING activation was shown to mediate kidney fibrosis through a non-canonical pathway (that is, independently of the cGAS–STING–TBK1–IRF3 pathway) 115 . In the unilateral ureteral obstruction model of kidney fibrosis, upon binding to cGAMP, STING was shown to interact directly with PKR-like ER kinase (PERK), which triggered phosphorylation of eukaryotic initiation factor 2α (eIF2α) and led to increased collagen expression and kidney fibrosis by modulating damage-initiated mRNA translation 115 . The cGAS–STING pathway has also been implicated in diabetic kidney disease 116 , where mitochondrial stress and release of mtDNA have important roles in disease pathogenesis 117 .…”

Section: Cgas–sting In Diseasementioning

confidence: 98%

See 1 more Smart Citation

Role of the cGAS–STING pathway in systemic and organ-specific diseases

2022

View full text Add to dashboard Cite

Cells are equipped with numerous sensors that recognize nucleic acids, which probably evolved for defence against viruses. Once triggered, these sensors stimulate the production of type I interferons and other cytokines that activate immune cells and promote an antiviral state. The evolutionary conserved enzyme cyclic GMP–AMP synthase (cGAS) is one of the most recently identified DNA sensors. Upon ligand engagement, cGAS dimerizes and synthesizes the dinucleotide second messenger 2′,3′-cyclic GMP–AMP (cGAMP), which binds to the endoplasmic reticulum protein stimulator of interferon genes (STING) with high affinity, thereby unleashing an inflammatory response. cGAS-binding DNA is not restricted by sequence and must only be >45 nucleotides in length; therefore, cGAS can also be stimulated by self genomic or mitochondrial DNA. This broad specificity probably explains why the cGAS–STING pathway has been implicated in a number of autoinflammatory, autoimmune and neurodegenerative diseases; this pathway might also be activated during acute and chronic kidney injury. Therapeutic manipulation of the cGAS–STING pathway, using synthetic cyclic dinucleotides or inhibitors of cGAMP metabolism, promises to enhance immune responses in cancer or viral infections. By contrast, inhibitors of cGAS or STING might be useful in diseases in which this pro-inflammatory pathway is chronically activated.

show abstract

Section: Cgas–sting In Diseasementioning

confidence: 98%

Section: Cgas–sting In Diseasementioning

confidence: 98%

Role of the cGAS–STING pathway in systemic and organ-specific diseases

2022

View full text Add to dashboard Cite

show abstract

“…Nucleic acids are predominant PAMPs and ubiquitous in living organisms. In addition to cytosolic DNA sensors such as cGAS and the critical roles of cGAS-STING signaling in cellular physiology [ 77 , 78 , 79 , 80 ], AIM2, thus far, is the sole sensor that detects cytosolic double-stranded DNA (dsDNA) among canonical inflammasome sensors [ 81 ]. Several independent groups identified AIM2 as a DNA-binding protein while searching for new DNA sensors, and found that it can activate caspase-1 and caspase-3 [ 82 ].…”

Section: Organization Of the Canonical Inflammasomesmentioning

confidence: 99%

Activation and Pharmacological Regulation of Inflammasomes

Chen

2022

Biomolecules

Self Cite

View full text Add to dashboard Cite

Inflammasomes are intracellular signaling complexes of the innate immune system, which is part of the response to exogenous pathogens or physiological aberration. The multiprotein complexes mainly consist of sensor proteins, adaptors, and pro-caspase-1. The assembly of the inflammasome upon extracellular and intracellular cues drives the activation of caspase-1, which processes pro-inflammatory cytokines IL-1β and IL-18 to maturation and gasdermin-D for pore formation, leading to pyroptosis and cytokine release. Inflammasome signaling functions in numerous infectious or sterile inflammatory diseases, including inherited autoinflammatory diseases, metabolic disorders, cardiovascular diseases, cancers, neurodegenerative disorders, and COVID-19. In this review, we summarized current ideas on the organization and activation of inflammasomes, with details on the molecular mechanisms, regulations, and interventions. The recent developments of pharmacological strategies targeting inflammasomes as disease therapeutics were also covered.

show abstract

“…On the opposite, reverse transcription of RNA viral genome can result in the host in the generation of dsDNA that lead to cGAS/STING activation, as reviewed in ( 81 ). An intriguing hypothesis emerging from recent literature is that activation of cGAS/STING in the presence of dsRNA is required to regulate cap-dependent mRNA translation ( 82 ) by acting at the level of PKR-like ER kinase (PERK) upstream of TBK1 to redirect ribosomes toward encoding pro-inflammatory factors ( 83 ).…”

Section: Ervs Intracellular Sensing and Signalingmentioning

confidence: 99%

“…More work is required to clarify whether these differential responses depend on the intensity and magnitude of the signaling pathways activated or on the differential signal transducers activated in the different contexts. Moreover, the integration of the RLR and cGAS/STING pathways ( 79 , 80 ) makes the analysis of the contribution of the different signaling molecules even more complex but reiterates the importance of nucleic acid sensors in regulating not only cellular innate immunity but also cellular fitness ( 83 ).…”

Section: Ervs In Cellular Senescence Neurodegeneration and Agingmentioning

confidence: 99%

Endogenous Retroviruses (ERVs): Does RLR (RIG-I-Like Receptors)-MAVS Pathway Directly Control Senescence and Aging as a Consequence of ERV De-Repression?

Giorgio

Xodo

2022

Front. Immunol.

View full text Add to dashboard Cite

Bi-directional transcription of Human Endogenous Retroviruses (hERVs) is a common feature of autoimmunity, neurodegeneration and cancer. Higher rates of cancer incidence, neurodegeneration and autoimmunity but a lower prevalence of autoimmune diseases characterize elderly people. Although the re-expression of hERVs is commonly observed in different cellular models of senescence as a result of the loss of their epigenetic transcriptional silencing, the hERVs modulation during aging is more complex, with a peak of activation in the sixties and a decline in the nineties. What is clearly accepted, instead, is the impact of the re-activation of dormant hERV on the maintenance of stemness and tissue self-renewing properties. An innate cellular immunity system, based on the RLR-MAVS circuit, controls the degradation of dsRNAs arising from the transcription of hERV elements, similarly to what happens for the accumulation of cytoplasmic DNA leading to the activation of cGAS/STING pathway. While agonists and inhibitors of the cGAS–STING pathway are considered promising immunomodulatory molecules, the effect of the RLR-MAVS pathway on innate immunity is still largely based on correlations and not on causality. Here we review the most recent evidence regarding the activation of MDA5-RIG1-MAVS pathway as a result of hERV de-repression during aging, immunosenescence, cancer and autoimmunity. We will also deal with the epigenetic mechanisms controlling hERV repression and with the strategies that can be adopted to modulate hERV expression in a therapeutic perspective. Finally, we will discuss if the RLR-MAVS signalling pathway actively modulates physiological and pathological conditions or if it is passively activated by them.

show abstract

A non-canonical cGAS–STING–PERK pathway facilitates the translational program critical for senescence and organ fibrosis

Cited by 130 publications

References 111 publications

Role of the cGAS–STING pathway in systemic and organ-specific diseases

Role of the cGAS–STING pathway in systemic and organ-specific diseases

Activation and Pharmacological Regulation of Inflammasomes

Endogenous Retroviruses (ERVs): Does RLR (RIG-I-Like Receptors)-MAVS Pathway Directly Control Senescence and Aging as a Consequence of ERV De-Repression?

Contact Info

Product

Resources

About