RIG-I-like receptors: their regulation and roles in RNA sensing

Rehwinkel, Jan; Gack, Michaela U.

doi:10.1038/s41577-020-0288-3

Cited by 1,023 publications

(1,036 citation statements)

References 238 publications

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“…In the aging kidneys, we found increased expression of STING and cGAS mRNAs and proteins, which was significantly reversed by treatment with the pan-ERR agonist ( Figure 7A). We also found similar changes with RNA sensors RIG-I/MDA5/LGP2 and other nucleic acid sensors, such as TLRs 64,65 (Figure 7B). We further examined the downstream response and we found out that expression of mRNA encoding components in NFκB signaling pathway (Rel, RelB, Nfkb2, and p65 protein) were increased in the aging kidney, and reduced by pan-ERR agonist treatment ( Figure 7C).…”

Section: Pan-err Agonist Treatment Decreased Inflammation In Aging Kisupporting

confidence: 74%

Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

Wang

Myakala

Libby

et al. 2019

Preprint

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ABSTRACTBackgroundA gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction and inflammation, which collectively contribute to age-related kidney dysfunction and disease. Here we studied the role of the nuclear hormone receptors, the estrogen-related receptors (ERRs) in regulation of age-related mitochondrial dysfunction and inflammation. ERRs were decreased in aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR).MethodsA pan-ERR agonist was used to treat 21-month-old mice for 8-weeks. In addition, 21-month-old mice were treated with a STING inhibitor for 3 weeks.ResultsRemarkably, only an 8-week treatment with a pan-ERR agonist reversed the age-related increases in albuminuria, podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker p21 but also unexpectedly reversed the age-related decreases in PGC-1α, ERRα, mitochondrial complexes and MCAD expression.ConclusionsOur studies identified ERRs as important modulators of age-related mitochondrial dysfunction and inflammation. These findings highlight novel druggable pathways that can be further evaluated to prevent progression of age-related kidney disease.Significance StatementThere is an increasing need for prevention and treatment strategies for age-related kidney disease. The hallmarks of aging kidneys are decreased mitochondrial function and increased inflammation. The expression of the nuclear hormone receptors estrogen-related receptors (ERRs) are decreased in aging human and mouse kidneys. This paper investigates the role of ERRs in the aging kidney. Treatment of aging mice with a pan-ERR agonist reversed the age-related increases in albuminuria and podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING signaling pathways. Treatment of aging mice with a STING inhibitor decreased inflammation and increased mitochondrial gene expression. These findings identify ERRs as important modulators of age-related mitochondrial dysfunction and inflammation.

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Section: Pan-err Agonist Treatment Decreased Inflammation In Aging Kisupporting

confidence: 74%

Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

Wang

Myakala

Libby

et al. 2019

Preprint

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“…LGP2, DHX58) belongs to the RLR family and acts as a modulatory co-receptor of RIG-I and MDA5 [315].…”

Section: Laboratory Of Genetics and Physiology 2 (mentioning

confidence: 99%

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

Eiermann

Haneke

Sun

et al. 2020

Viruses

117

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Cells have evolved highly specialized sentinels that detect viral infection and elicit an antiviral response. Among these, the stress-sensing protein kinase R, which is activated by double-stranded RNA, mediates suppression of the host translation machinery as a strategy to limit viral replication. Non-translating mRNAs rapidly condensate by phase separation into cytosolic stress granules, together with numerous RNA-binding proteins and components of signal transduction pathways. Growing evidence suggests that the integrated stress response, and stress granules in particular, contribute to antiviral defense. This review summarizes the current understanding of how stress and innate immune signaling act in concert to mount an effective response against virus infection, with a particular focus on the potential role of stress granules in the coordination of antiviral signaling cascades.

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“…In the cytosol, viral RNA and aberrant small endogenous RNAs are recognized by retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), followed by aggregation of mitochondrial antiviral-signaling protein (MAVS) and the subsequent activation of the transcription factors nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3). [6][7][8][9] DNA usually resides in the nucleus and mitochondria in eukaryotic cells. The aberrant presence of DNA in cytoplasm either from infection or cellular damage elicits robust immune responses leading to inflammasome activation and transcription of genes encoding type I interferon (IFN) and inflammation, which are both beneficial and detrimental to the host.…”

Section: F I G U R Ementioning

confidence: 99%

The cGAS‐STING pathway: The role of self‐DNA sensing in inflammatory lung disease

Serrano

Davis

et al. 2020

FASEB j.

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The presence of DNA in the cytosol is usually a sign of microbial infections, which alerts the host innate immune system to mount a defense response. Cyclic GMP‐AMP synthase (cGAS) is a critical cytosolic DNA sensor that elicits robust innate immune responses through the production of the second messenger, cyclic GMP‐AMP (cGAMP), which binds and activates stimulator of interferon genes (STING). However, cGAS binds to DNA irrespective of DNA sequence, therefore, self‐DNA leaked from the nucleus or mitochondria can also serve as a cGAS ligand to activate this pathway and trigger extensive inflammatory responses. Dysregulation of the cGAS‐STING pathway is responsible for a broad array of inflammatory and autoimmune diseases. Recently, evidence has shown that self‐DNA release and cGAS‐STING pathway over‐activation can drive lung disease, making this pathway a promising therapeutic target for inflammatory lung disease. Here, we review recent advances on the cGAS‐STING pathway governing self‐DNA sensing, highlighting its role in pulmonary disease.

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RIG-I-like receptors: their regulation and roles in RNA sensing

Cited by 1,023 publications

References 238 publications

Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

The cGAS‐STING pathway: The role of self‐DNA sensing in inflammatory lung disease

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