ABCE1 Acts as a Positive Regulator of Exogenous RNA Decay

Ogami, Koichi; Oishi, Yuka; Goda, Ryoya; Hosoda, Naoe; Kitamura, Yoshiaki; Kitade, Yukio; Hoshino, Shin‐ichi

doi:10.3390/v12020174

Cited by 5 publications

(6 citation statements)

References 32 publications

(70 reference statements)

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“…It is not clear if transfected exogenous RNAs are processed differently from the endogenous RNAs cleaved in the cellular context and during viral infections. In line with other studies on RNase L activation, in our studies, the ligand 2-5A was delivered by complexing with lipid reagents, in contrast to the electroporation-mediated delivery used by Nogimori et al [ 40 ]. Furthermore, basal levels of OAS proteins and RNase L vary by cell types and are determinants of IFN induction during viral infection, including EMCV [ 64 ].…”

Section: Discussionsupporting

confidence: 75%

“…The effects of ABCE1 on inhibiting RNase L is specific as cells lacking both proteins show no nucleolytic activity. In contrast, another recent study showed the interaction of ABCE1 with Dom34 (Pelota) and RNase L to function as a positive regulator of exogenous RNA decay [ 40 ]. It is not clear if transfected exogenous RNAs are processed differently from the endogenous RNAs cleaved in the cellular context and during viral infections.…”

Section: Discussionmentioning

confidence: 99%

“…RLI was initially identified as a negative regulator of RNase L by directly binding to RNase L and inhibiting the binding of 2-5A [ 38 , 39 ]. In contrast, a recent study showed that the interaction of ABCE1 with RNase L accelerates dimerization and acts as a positive regulator of exogenous RNA decay [ 40 ]. ABCE1 is induced by EMCV and HIV and may serve as a mechanism to evade the antiviral effects of RNase L [ 41 , 42 ].…”

Section: Introductionmentioning

confidence: 99%

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ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections

Ramnani

Manivannan

Jaggernauth

et al. 2021

Viruses

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Host response to a viral infection includes the production of type I interferon (IFN) and the induction of interferon-stimulated genes that have broad antiviral effects. One of the key antiviral effectors is the IFN-inducible oligoadenylate synthetase/ribonuclease L (OAS/RNase L) pathway, which is activated by double-stranded RNA to synthesize unique oligoadenylates, 2-5A, to activate RNase L. RNase L exerts an antiviral effect by cleaving diverse RNA substrates, limiting viral replication; many viruses have evolved mechanisms to counteract the OAS/RNase L pathway. Here, we show that the ATP-binding cassette E1 (ABCE1) transporter, identified as an inhibitor of RNase L, regulates RNase L activity and RNase L-induced autophagy during viral infections. ABCE1 knockdown cells show increased RNase L activity when activated by 2-5A. Compared to parental cells, the autophagy-inducing activity of RNase L in ABCE1-depleted cells is enhanced with early onset. RNase L activation in ABCE1-depleted cells inhibits cellular proliferation and sensitizes cells to apoptosis. Increased activity of caspase-3 causes premature cleavage of autophagy protein, Beclin-1, promoting a switch from autophagy to apoptosis. ABCE1 regulates autophagy during EMCV infection, and enhanced autophagy in ABCE1 knockdown cells promotes EMCV replication. We identify ABCE1 as a host protein that inhibits the OAS/RNase L pathway by regulating RNase L activity, potentially affecting antiviral effects.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections

Ramnani

Manivannan

Jaggernauth

et al. 2021

Viruses

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“…Next, we wanted to assess what changes directly result from the global RNA cleavage that occurs after RNase L activation. RNase L is known to interact with several proteins, including those that make up the cytoskeleton and the nucleopore complex (Bisbal et al, 1995; Burke et al, 2021; Le Roy et al, 2005; Nogimori et al, 2019; Nogimori et al, 2020; Tnani et al, 1998). Thus, it is possible that some of the observed changes upon RNase L activation and dimerization arise from functional protein-protein interactions and not RNA cleavage.…”

Section: Resultsmentioning

confidence: 99%

Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response

Karasik,

Lorenzi,

DePass

et al. 2023

Preprint

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SummaryDuring viral infection, several dsRNA sensors are activated in the cell and trigger signaling that leads to changes in gene expression. One of these sensors activates an endonuclease, RNase L, that cleaves many types of RNA in the cell. However, how the resultant widespread RNA decay affects gene expression is not fully understood. Here we found that gene expression changes caused by activating dsRNA sensing pathways are tuned by RNase L activation, pointing to intricacy in the innate immune response where multiple inputs are integrated to create an optimized output. We show that RNase-L-dependent RNA fragmentation induces the activation of the Ribotoxic Stress Response, potentially through ribosome collisions. The p38 and JNK pathways that are activated as part of this response promote outcomes that inhibit the virus, such as programmed cell death. We also show that RNase L appears to limit the translation of genes that are regulated by another dsRNA-induced pathway, the Integrated Stress Response. Intriguingly, we found the activity of the generic endonuclease, RNase A, recapitulates many of the same molecular phenotypes as activated RNase L, demonstrating how widespread RNA cleavage events can directly evoke an antiviral program.Key summaryActivated RNase L acts together with other dsRNA-sensing pathways to induce a strong immune response via JNK and p38 signalingGeneric RNA fragmentation plays a key role in inducing transcription, potentially through ribosome collisionsActivation of RNase L inhibits the effects of eIF2α phosphorylationTranslation of the antiviral IFIT mRNAs is inhibited by active RNase L

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“…Previous studies suggest the action of ABCE1 together with RNAse L to eliminate exogenous RNA [ 96 ]. Taken together, the present data provide evidence for the regulation of the 2’-5’ OAS pathway independent of ABCE1 and RNAse L, providing support for a key role of this pathway in the immune response in infections by LbLRV1+ parasites.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomics analysis highlights potential ways in human pathogenesis in Leishmania braziliensis infected with the viral endosymbiont LRV1

Felipin,

Paloschi,

Silva

et al. 2024

PLoS Negl Trop Dis

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The parasite Leishmania (Viannia) braziliensis is widely distributed in Brazil and is one of the main species associated with human cases of different forms of tegumentary leishmaniasis (TL) such as cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML). The mechanisms underlying the pathogenesis of TL are still not fully understood, but it is known that factors related to the host and the parasite act in a synergistic and relevant way to direct the response to the infection. In the host, macrophages have a central connection with the parasite and play a fundamental role in the defense of the organism due to their ability to destroy intracellular parasites and present antigens. In the parasite, some intrinsic factors related to the species or even the strain analyzed are fundamental for the outcome of the disease. One of them is the presence of Leishmania RNA Virus 1 (LRV1), an endosymbiont virus that parasitizes some species of Leishmania that triggers a cascade of signals leading to a more severe TL phenotype, such as ML. One of the strategies for understanding factors associated with the immune response generated after Leishmania/host interaction is through the analysis of molecular patterns after infection. Thus, the gene expression profile in human monocyte-derived macrophages obtained from healthy donors infected in vitro with L. braziliensis positive (LbLRV1+) and negative (LbLRV1-) for LRV1 was evaluated. For this, the microarray assay was used and 162 differentially expressed genes were identified in the comparison LbLRV1+ vs. LbLRV1-, 126 upregulated genes for the type I and II interferons (IFN) signaling pathway, oligoadenylate synthase OAS/RNAse L, non-genomic actions of vitamin D3 and RIG-I type receptors, and 36 down-regulated. The top 10 downregulated genes along with the top 10 upregulated genes were considered for analysis. Type I interferon (IFNI)- and OAS-related pathways results were validated by RT-qPCR and Th1/Th2/Th17 cytokines were analyzed by Cytometric Bead Array (CBA) and enzyme-linked immunosorbent assay (ELISA). The microarray results validated by RT-qPCR showed differential expression of genes related to IFNI-mediated pathways with overexpression of different genes in cells infected with LbLRV1+ compared to LbLRV1- and to the control. No significant differences were found in cytokine levels between LbLRV1+ vs. LbLRV1- and control. The data suggest the activation of gene signaling pathways associated with the presence of LRV1 has not yet been reported so far. This study demonstrates, for the first time, the activation of the OAS/RNase L signaling pathway and the non-genomic actions of vitamin D3 when comparing infections with LbLRV1+ versus LbLRV1- and the control. This finding emphasizes the role of LRV1 in directing the host’s immune response after infection, underlining the importance of identifying LRV1 in patients with TL to assess disease progression.

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ABCE1 Acts as a Positive Regulator of Exogenous RNA Decay

Cited by 5 publications

References 32 publications

ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections

ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections

Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response

Transcriptomics analysis highlights potential ways in human pathogenesis in Leishmania braziliensis infected with the viral endosymbiont LRV1

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