A novel selective autophagy receptor, CCDC50, delivers K63 polyubiquitination-activated RIG-I/MDA5 for degradation during viral infection

Hou, Panpan; Yang, Keda; Jia, Ping; Liu, Lan; Lin, Yuxin; Li, Zibo; Li, Jun; Chen, Shuliang; Guo, Shuting; Pan, Jian; Wu, Junyu; Hong, Peng; Zeng, Wenjing; Liu, Yingfang; Guo, Deyin

doi:10.1038/s41422-020-0362-1

Cited by 60 publications

(43 citation statements)

References 50 publications

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“…The N-terminus contains a CARD-like domain, which binds to RIG-I and MDA-5 through the CARD–CARD interaction. 271 , 272 The proline-enriched domain in MAVS can interact with a series of downstream signaling molecules, such as TRAF3 and 6, 273 and activate the protein kinase IKK, which causes phosphorylation of IκB, 265 and then IκB is ubiquitinated and degraded by proteases, activating the NF-κB pathway. 274 …”

Section: Signaling Pathways Of Prrsmentioning

confidence: 99%

Pattern recognition receptors in health and diseases

2021

Sig Transduct Target Ther

572

301

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Pattern recognition receptors (PRRs) are a class of receptors that can directly recognize the specific molecular structures on the surface of pathogens, apoptotic host cells, and damaged senescent cells. PRRs bridge nonspecific immunity and specific immunity. Through the recognition and binding of ligands, PRRs can produce nonspecific anti-infection, antitumor, and other immunoprotective effects. Most PRRs in the innate immune system of vertebrates can be classified into the following five types based on protein domain homology: Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs). PRRs are basically composed of ligand recognition domains, intermediate domains, and effector domains. PRRs recognize and bind their respective ligands and recruit adaptor molecules with the same structure through their effector domains, initiating downstream signaling pathways to exert effects. In recent years, the increased researches on the recognition and binding of PRRs and their ligands have greatly promoted the understanding of different PRRs signaling pathways and provided ideas for the treatment of immune-related diseases and even tumors. This review describes in detail the history, the structural characteristics, ligand recognition mechanism, the signaling pathway, the related disease, new drugs in clinical trials and clinical therapy of different types of PRRs, and discusses the significance of the research on pattern recognition mechanism for the treatment of PRR-related diseases.

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Section: Signaling Pathways Of Prrsmentioning

confidence: 99%

Pattern recognition receptors in health and diseases

2021

Sig Transduct Target Ther

572

301

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“…The screen precisely identified several known regulators such as RIG-I (29), PSMB11 (30), SPNS2 (31), IRF3/IRF7 (32), IFIH1 (33), LCK (34), TRIM33 (35), and ATG12 (36) of immune signaling or development of immune cells, indicating that the screen was effectively executed. Among the top ranked genes, there are several that were previously unknown to be involved in immune and inflammatory responses, including CCDC50, which is a novel autophagic substrate receptor involved in negative regulation of RIG-I-mediated interferon signaling published very recently by our group (37), and ASB1 which was previously regarded as a substrate-recognition component of an E3 ligase complex for ubiquitination and proteasomal degradation (38). As the function of ASB1 had not been characterized previously, we went further to validate the function of ASB1 in type I IFN-mediated antiviral innate immune and inflammatory responses.…”

Section: Resultsmentioning

confidence: 99%

An unconventional role of an ASB family protein in NF-κB activation and inflammatory response during microbial infection and colitis

Hou

Jia

Yang

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear factor κB (NF-κB)–mediated signaling pathway plays a crucial role in the regulation of inflammatory process, innate and adaptive immune responses. The hyperactivation of inflammatory response causes host cell death, tissue damage, and autoinflammatory disorders, such as sepsis and inflammatory bowel disease. However, how these processes are precisely controlled is still poorly understood. In this study, we demonstrated that ankyrin repeat and suppressor of cytokine signaling box containing 1 (ASB1) is involved in the positive regulation of inflammatory responses by enhancing the stability of TAB2 and its downstream signaling pathways, including NF-κB and mitogen-activated protein kinase pathways. Mechanistically, unlike other members of the ASB family that induce ubiquitination-mediated degradation of their target proteins, ASB1 associates with TAB2 to inhibit K48-linked polyubiquitination and thereby promote the stability of TAB2 upon stimulation of cytokines and lipopolysaccharide (LPS), which indicates that ASB1 plays a noncanonical role to further stabilize the target protein rather than induce its degradation. The deficiency of Asb1 protects mice from Salmonella typhimurium– or LPS-induced septic shock and increases the survival of mice. Moreover, Asb1-deficient mice exhibited less severe colitis and intestinal inflammation induced by dextran sodium sulfate. Given the crucial role of ASB proteins in inflammatory signaling pathways, our study offers insights into the immune regulation in pathogen infection and inflammatory disorders with therapeutic implications.

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“…Therefore, we hypothesized that the type I IFN pathway may be activated by the binding of PPE57 to the type I IFN receptor (IFNAR1 and IFNAR2), subsequently regulating the activation of ISGs and other signaling pathways. PPE57 was also able to influence RLR pathway signaling, which controls type I IFN signaling pathway activation ( Hou et al., 2021 ). RLRs include RIG-I, MDA5, and LGP2, all of which play important roles in the recognition of viral RNA in the cytoplasm ( Bruns and Horvath, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Profiling of Human Peripheral Blood Mononuclear Cells Stimulated by Mycobacterium tuberculosis PPE57 Identifies Characteristic Genes Associated With Type I Interferon Signaling

Zhu

et al. 2021

Front. Cell. Infect. Microbiol.

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Proline-glutamic acid (PE)- and proline-proline-glutamic acid (PPE)-containing proteins are exclusive to Mycobacterium tuberculosis (MTB), the leading cause of tuberculosis (TB). In this study, we performed global transcriptome sequencing (RNA-Seq) on PPE57-stimulated peripheral blood mononuclear cells (PBMCs) and control samples to quantitatively measure the expression level of key transcripts of interest. A total of 1367 differentially expressed genes (DEGs) were observed in response to a 6 h exposure to PPE57, with 685 being up-regulated and 682 down-regulated. Immune-related gene functions and pathways associated with these genes were evaluated, revealing that the type I IFN signaling pathway was the most significantly enriched pathway in our RNA-seq dataset, with 14 DEGs identified therein including ISG15, MX2, IRF9, IFIT3, IFIT2, OAS3, IFIT1, IFI6, OAS2, OASL, RSAD2, OAS1, IRF7, and MX1. These PPE57-related transcriptomic profiles have implications for a better understanding of host global immune mechanisms underlying MTB infection outcomes. However, more studies regarding these DEGs and type I IFN signaling in this infectious context are necessary to more fully clarify the underlying mechanisms that arise in response to PPE57 during MTB infection.

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A novel selective autophagy receptor, CCDC50, delivers K63 polyubiquitination-activated RIG-I/MDA5 for degradation during viral infection

Cited by 60 publications

References 50 publications

Pattern recognition receptors in health and diseases

Pattern recognition receptors in health and diseases

An unconventional role of an ASB family protein in NF-κB activation and inflammatory response during microbial infection and colitis

Transcriptional Profiling of Human Peripheral Blood Mononuclear Cells Stimulated by Mycobacterium tuberculosis PPE57 Identifies Characteristic Genes Associated With Type I Interferon Signaling

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