Autophagy receptor CCDC50 tunes the STING-mediated interferon response in viral infections and autoimmune diseases

Hou, Panpan; Lin, Yuxin; Li, Zibo; Lu, Ruiqing; Wang, Yicheng; Tian, Tian; Jia, Ping; Zhang, Xi; Cao, Liu; Zhou, Zhongwei; Li, Chunmei; J, Gu; Guo, Deyin

doi:10.1038/s41423-021-00758-w

Cited by 30 publications

(22 citation statements)

References 71 publications

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“…To define the physiological significance of CCDC50 in vivo , we investigated the inflammasome signaling in Ccdc50 ‐knockout ( Ccdc50 −/− ) mice generated by the CRISPR/Cas9 system (Hou et al , 2021a). The genotypes of mice were verified by PCR and sequencing (Fig EV2A).…”

Section: Resultsmentioning

confidence: 99%

“…Human CCDC50 is highly expressed in immune tissues and cells, which is closely related to RLR-and cGAS-STING-mediated immune and inflammatory signaling pathways (Worah et al, 2016;Hou et al, 2021aHou et al, , 2021b To further explore CCDC50-regulated genes, we performed RNA-sequencing (RNA-seq) experiment and differential expression (DE) analysis. Compared to cells treated with negative control shRNA, 213 genes were significantly differentially expressed in CCDC50-deficient cells, including 129 upregulated genes and 84 downregulated genes (Fig 1A).…”

Section: Ccdc50 Deficiency Enhances the Activity Of Inflammatory Sign...mentioning

confidence: 99%

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CCDC50 suppresses NLRP3 inflammasome activity by mediating autophagic degradation of NLRP3

Lin

Wang

et al. 2022

EMBO Reports

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The NLRP3‐directed inflammasome complex is crucial for the host to resist microbial infection and monitor cellular damage. However, the hyperactivation of NLRP3 inflammasome is implicated in pathogenesis of inflammatory diseases, including inflammatory bowel disease (IBD). Autophagy and autophagy‐related genes are closely linked to NLRP3‐mediated inflammation in these inflammatory disorders. Here, we report that CCDC50, a novel autophagy cargo receptor, negatively regulates NLRP3 inflammasome assembly and suppresses the cleavage of pro‐caspase‐1 and interleukin 1β (IL‐1β) release by delivering NLRP3 for autophagic degradation. Transcriptome analysis showed that knockdown of CCDC50 results in upregulation of signaling pathways associated with autoinflammatory diseases. CCDC50 deficiency leads to enhanced proinflammatory cytokine response triggered by a wide range of endogenous and exogenous NLRP3 stimuli. Ccdc50‐deficient mice are more susceptible to dextran sulfate (DSS)‐induced colitis and exhibit more severe gut inflammation with elevated NLRP3 inflammasome activity. These results illustrate the physiological significance of CCDC50 in the pathogenicity of inflammatory diseases, suggesting protective roles of CCDC50 in keeping gut inflammation under control.

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Section: Resultsmentioning

confidence: 99%

Section: Ccdc50 Deficiency Enhances the Activity Of Inflammatory Sign...mentioning

confidence: 99%

CCDC50 suppresses NLRP3 inflammasome activity by mediating autophagic degradation of NLRP3

Lin

Wang

et al. 2022

EMBO Reports

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“…However, in HeLa cells, the autophagy receptor coiled-coil domain containing 50 (CCDC50) binds to and targets K63-polyubiquitinated STING1 for autophagic degradation. Studies reveal that CCDC50 mainly mediates the delivery of STING1 to MAP1LC3-positive autophagosomes, rather than directly promoting STING1 degradation in lysosomes ( 78 ). Therefore, each step of selective autophagy degradation of STING1 may require different autophagy receptors to mediate.…”

Section: Roles Of Sting1 In Organellesmentioning

confidence: 99%

STING1 in Different Organelles: Location Dictates Function

2022

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Stimulator of interferon response cGAMP interactor 1 (STING1), also known as TMEM173, is an immune adaptor protein that governs signal crosstalk that is implicated in many physiological and pathological processes. Although it has been established that STING1 traffics from the endoplasmic reticulum (ER) to Golgi apparatus (Golgi) upon DNA-triggered activation, emerging evidence reveals that STING1 can be transported to different organelles, which dictate its immune-dependent (e.g., the production of type I interferons and pro-inflammatory cytokines) and -independent (e.g., the activation of autophagy and cell death) functions. In this brief review, we outline the roles of STING1 in different organelles (including the ER, ER-Golgi intermediate compartment, Golgi, mitochondria, endosomes, lysosomes, and nucleus) and discuss the potential relevance of these roles to diseases and pharmacological interventions.

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“…Intriguingly, a recent observation reveals that a novel autophagy receptor, CCDC50, can recognize K63-polyubiquitinated STING for autophagic degradation, which inhibits IFN-I and pro-inflammatory cytokines production. Moreover, CCDC50 deficiency restricts HSV-1 replication, which shows a possible therapeutic strategy to prevent viral evasion ( Hou et al, 2021 ).…”

Section: Post-translational Modification Of Cyclic Gmp-amp Synthase-stimulator Of Interferon Genes Pathway Components Is Significant To Amentioning

confidence: 99%

The Regulatory Network of Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Pathway in Viral Evasion

et al. 2021

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Virus infection has been consistently threatening public health. The cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway is a critical defender to sense various pathogens and trigger innate immunity of mammalian cells. cGAS recognizes the pathogenic DNA in the cytosol and then synthesizes 2′3′-cyclic GMP-AMP (2′3′cGAMP). As the second messenger, cGAMP activates STING and induces the following cascade to produce type I interferon (IFN-I) to protect against infections. However, viruses have evolved numerous strategies to hinder the cGAS-STING signal transduction, promoting their immune evasion. Here we outline the current status of the viral evasion mechanism underlying the regulation of the cGAS-STING pathway, focusing on how post-transcriptional modifications, viral proteins, and non-coding RNAs involve innate immunity during viral infection, attempting to inspire new targets discovery and uncover potential clinical antiviral treatments.

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Autophagy receptor CCDC50 tunes the STING-mediated interferon response in viral infections and autoimmune diseases

Cited by 30 publications

References 71 publications

CCDC50 suppresses NLRP3 inflammasome activity by mediating autophagic degradation of NLRP3

CCDC50 suppresses NLRP3 inflammasome activity by mediating autophagic degradation of NLRP3

STING1 in Different Organelles: Location Dictates Function

The Regulatory Network of Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Pathway in Viral Evasion

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