TDP-43 prevents endogenous RNAs from triggering a lethal RIG-I-dependent interferon response

Dunker, William; Ye, Xiang; Zhao, Yang; Liu, Lanxi; Richardson, Antiana; Karijolich, John

doi:10.1016/j.celrep.2021.108976

Cited by 32 publications

(28 citation statements)

References 76 publications

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“…For example, while RIG-I can be stimulated by unedited RNA lacking 6-methyladenosine ( 12 ), it can also be actively antagonized by RNAs containing 5′-monophosphates (5′-p RNAs), which are abundant in healthy cells and therefore represent a gating mechanism to prevent basal activation to self-RNA species ( 32 ). The RNA-binding protein TAR DNA-binding protein 43 has also been reported to prevent accumulation of endogenous RNA species that can activate RIG-I ( 33 ). If SF3B1 modulation increases unedited RNA lacking 6-methyladenosine or in contrast decreases RNAs containing 5′-monophosphates or decreases TAR DNA-binding protein 43 expression, these can also represent mechanisms to induce RIG-I activation.…”

Section: Discussionmentioning

confidence: 99%

Modulation of SF3B1 in the pre-mRNA spliceosome induces a RIG-I-dependent type I IFN response

Chang

Zhou

Iyengar

et al. 2021

Journal of Biological Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

show abstract

Section: Discussionmentioning

confidence: 99%

Modulation of SF3B1 in the pre-mRNA spliceosome induces a RIG-I-dependent type I IFN response

Chang

Zhou

Iyengar

et al. 2021

Journal of Biological Chemistry

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“…Multiple lines of evidence demonstrated that TDP43 is a DNA/RNA-binding protein involved in RNA metabolism including the NOTCH1 mRNA. 24 – 26 Indeed, silencing of LCETRL3 induced significantly downregulated NOTCH1 expression in both the PC9 and H1299 cells (shL3-1 and shL3-2 vs. shNC; P < 0.05) (Fig. 4 j and k ).…”

Section: Resultsmentioning

confidence: 91%

“…We revealed that lncRNA LCETRL3 can interact with TDP43 protein and suppress degradation of TDP43, an RNA-binding protein that participates in multiple steps of RNA metabolism, including transcription, splicing, and transport of mRNA, as well as miRNA metabolism. 24 TDP43 has been shown to promote growth and metastasis of NSCLC, triple-negative breast cancer, neuroblastoma, hepatocellular carcinoma and melanoma. 35 – 40 Consistently, we found that TDP43 was significantly upregulated in NSCLC tissues.…”

Section: Discussionmentioning

confidence: 99%

LncRNAs LCETRL3 and LCETRL4 at chromosome 4q12 diminish EGFR-TKIs efficiency in NSCLC through stabilizing TDP43 and EIF2S1

Shen

Xie

et al. 2022

Sig Transduct Target Ther

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Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are effective targeted therapy drugs for advanced non-small cell lung cancer (NSCLC) patients carrying sensitized EGFR mutations. The rapid development of EGFR-TKIs resistance represents a major clinical challenge for managing NSCLC. The chromosome 4q12 is the first genome-wide association study (GWAS)-reported locus associated with progression-free survival (PFS) of NSCLC patients treated with EGFR-TKIs. However, the biological significance of the noncoding transcripts at 4q12 in NSCLC remains elusive. In the present study, we identified two 4q12 long noncoding RNAs (lncRNAs) LCETRL3 and LCETRL4 which could significantly dimmish EGFR-TKIs efficiency. In line with their oncogenic role, evidently higher LCETRL3 and LCETRL4 levels were observed in NSCLC tissues as compared with normal specimens. Importantly, lncRNA LCETRL3 can interact with oncoprotein TDP43 and inhibit ubiquitination and degradation of TDP43. Similarly, lncRNA LCETRL4 can bind and stabilize oncoprotein EIF2S1 through reducing ubiquitin-proteasome degradation of EIF2S1. In particular, elevated levels of LCETRL3 or LCETRL4 in NSCLC cells resulted in stabilization of TDP43 or EIF2S1, increased levels of NOTCH1 or phosphorylated PDK1, activated AKT signaling and, thus, EGFR-TKIs resistance. Taken together, our data revealed a novel model that integrates two lncRNAs transcribed from the 4q12 locus into the regulation of EGFR-TKIs resistance in NSCLC. These findings shed new light on the importance of functionally annotating lncRNAs in the GWAS loci and provided insights to declare novel druggable targets, i.e., lncRNAs, which may unlock the therapeutic potential of EGFR-TKIs resistant NSCLC in the clinic.

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“…Induction of apoptosis by RIG-I and MDA5 is mediated through a unique mechanism known as RLR-induced IRF3-mediated pathway of apoptosis (RIPA), during which TRAF2, TRAF6, and a linear ubiquitin chain assembly complex (LUBAC) are recruited to modify IRF3, leading to its subsequent translocation with Bax to mitochondria ( Chattopadhyay et al 2010 , 2016 ). Furthermore, RIG-I-dependent IFN response also promotes RIPK3-mediated necroptosis ( Brault et al 2018 ; Dunker et al 2021 ). In many cases, the activation of inflammasome and cell death programs might either exert a protective role by eliminating the virus-infected cells or facilitate virus dissemination and spread by releasing a large number of virion particles.…”

Section: Introductionmentioning

confidence: 99%

Cytoplasmic RNA sensors and their interplay with RNA-binding partners in innate antiviral response: theme and variations

Chan

Jin

2022

RNA

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Sensing of pathogen-associated molecular patterns including viral RNA by innate immunity represents the first line of defense against viral infection. In addition to RIG-I-like receptors and NOD-like receptors, several other RNA sensors are known to mediate innate antiviral response in the cytoplasm. Double-stranded RNA-binding protein PACT interacts with prototypic RNA sensor RIG-I to facilitate its recognition of viral RNA and induction of host interferon response, but variations of this theme are seen when the functions of RNA sensors are modulated by other RNA-binding proteins to impinge on antiviral defense, proinflammatory cytokine production and cell death programs. Their discrete and coordinated actions are crucial to protect the host from infection. In this review, we will focus on cytoplasmic RNA sensors with an emphasis on their interplay with RNA-binding partners. Classical sensors such as RIG-I will be briefly reviewed. More attention will be brought to the new insights on how RNA-binding partners of RNA sensors modulate innate RNA sensing and how viruses perturb the functions of RNA-binding partners.

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TDP-43 prevents endogenous RNAs from triggering a lethal RIG-I-dependent interferon response

Cited by 32 publications

References 76 publications

Modulation of SF3B1 in the pre-mRNA spliceosome induces a RIG-I-dependent type I IFN response

Modulation of SF3B1 in the pre-mRNA spliceosome induces a RIG-I-dependent type I IFN response

LncRNAs LCETRL3 and LCETRL4 at chromosome 4q12 diminish EGFR-TKIs efficiency in NSCLC through stabilizing TDP43 and EIF2S1

Cytoplasmic RNA sensors and their interplay with RNA-binding partners in innate antiviral response: theme and variations

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