Cleavage of IPS-1 in Cells Infected with Human Rhinovirus

Drahos, Jennifer; Racaniello, Vincent R.

doi:10.1128/jvi.01490-09

Cited by 79 publications

(82 citation statements)

References 37 publications

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“…Previous studies have reported that picornaviruses exert various strategies to evade host innate immune responses through certain viral proteins, such as L pro , VP2, VP3, 2A pro , 2C pro , 3A pro , and 3C pro (17,18,(25)(26)(27)(28)(29)(30)(31). In this study, we found that the overexpression of SVV proteins VP2, 3C pro , and 3D reduced Sev-induced IFN-␤ production (Fig.…”

Section: Resultssupporting

confidence: 59%

Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage

Qian

Fan

Liu

et al. 2017

J Virol

107

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Seneca Valley virus (SVV) is an oncolytic RNA virus belonging to the Picornaviridae family. Its nucleotide sequence is highly similar to those of members of the Cardiovirus genus. SVV is also a neuroendocrine cancer-selective oncolytic picornavirus that can be used for anticancer therapy. However, the interaction between SVV and its host is yet to be fully characterized. In this study, SVV inhibited antiviral type I interferon (IFN) responses by targeting different host adaptors, including mitochondrial antiviral signaling (MAVS), Toll/interleukin 1 (IL-1) receptor domain-containing adaptor inducing IFN-␤ (TRIF), and TRAF family member-associated NF-B activator (TANK), via viral 3C protease (3C pro ). SVV 3C pro mediated the cleavage of MAVS, TRIF, and TANK at specific sites, which required its protease activity. The cleaved MAVS, TRIF, and TANK lost the ability to regulate pattern recognition receptor (PRR)-mediated IFN production. The cleavage of TANK also facilitated TRAF6-induced NF-B activation. SVV was also found to be sensitive to IFN-␤. Therefore, SVV suppressed antiviral IFN production to escape host antiviral innate immune responses by cleaving host adaptor molecules. IMPORTANCE Host cells have developed various defenses against microbial pathogen infection. The production of IFN is the first line of defense against microbial infection. However, viruses have evolved many strategies to disrupt this host defense. SVV, a member of the Picornavirus genus, is an oncolytic virus that shows potential functions in anticancer therapy. It has been demonstrated that IFN can be used in anticancer therapy for certain tumors. However, the relationship between oncolytic virus and innate immune response in anticancer therapy is still not well known. In this study, we showed that SVV has evolved as an effective mechanism to inhibit host type I IFN production by using its 3C pro to cleave the molecules MAVS, TRIF, and TANK directly. These molecules are crucial for the Toll-like receptor 3 (TLR3)-mediated and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-mediated signaling pathway. We also found that SVV is sensitive to IFN-␤. These findings increase our understanding of the interaction between SVV and host innate immunity.

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Section: Resultssupporting

confidence: 59%

Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage

Qian

Fan

Liu

et al. 2017

J Virol

107

View full text Add to dashboard Cite

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“…Studies with polio-and rhinovirus have suggested that reduced expression of IPS1 is dependent on the activation of cellular caspases (Drahos & Racaniello, 2009;Rebsamen et al, 2008). However, using a caspase inhibitor we demonstrated that the CVB3-induced reduction of TRIF and IPS1 expression was not dependent on caspase activation (Fig.…”

Section: Discussionmentioning

confidence: 65%

“…Some enteroviruses including poliovirus have been shown previously to induce proteasome-and/or caspase-dependent degradation of MDA5 (Barral et al, 2007;Drahos & Racaniello, 2009;Rebsamen et al, 2008).…”

Section: Cvb3 Infection Negatively Affects the Protein Expression Levmentioning

confidence: 99%

Coxsackievirus counters the host innate immune response by blocking type III interferon expression

Lind

Svedin

Domsgen

et al. 2016

Journal of General Virology

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Type I IFNs play an important role in the immune response to enterovirus infections. Their importance is underscored by observations showing that many enteroviruses including coxsackie B viruses (CVBs) have developed strategies to block type I IFN production. Recent studies have highlighted a role for the type III IFNs (also called IFNls) in reducing permissiveness to infections with enteric viruses including coxsackievirus. However, whether or not CVBs have measures to evade the effects of type III IFNs remains unknown. By combining virus infection studies and different modes of administrating the dsRNA mimic poly I : C, we discovered that CVBs target both Toll-like receptor 3-and MDA5/RIG-I-mediated type III IFN expression. Consistent with this, the cellular protein expression levels of the signal transduction proteins TRIF and IPS1 were reduced and no hyperphosphorylation of interferon regulatory factor 3 was observed following infection with the virus. Notably, decreased expression of full-length TRIF and IPS1 and the appearance of cleavage products was observed upon both CVB3 infection and in cellular protein extracts incubated with recombinant 2A pro , indicating an important role for the viral protease in subverting the cellular immune system. Collectively, our study reveals that CVBs block the expression of type III IFNs, and that this is achieved by a similar mechanism as the virus uses to block type I IFN production. We also demonstrate that the virus blocks several intracellular viral recognition pathways of importance for both type I and III IFN production. The simultaneous targeting of numerous arms of the host immune response may be required for successful viral replication and dissemination.

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“…Picornavirus infection can affect host mechanisms, such as host cap-dependent translation (11,12), transcription (13,14), and immune responses (15)(16)(17). For example, viral protease 2A pro can cleave eukaryotic initiation factor 4G (eIF4G) (18)(19)(20), poly(A)-binding protein (PABP) (21,22), beta interferon (IFN-␤) promoter stimulator-1 (IPS-1) (17), and 62-kDa nucleoporin (Nup62) (23).…”

mentioning

confidence: 99%

Enterovirus 71 Infection Cleaves a Negative Regulator for Viral Internal Ribosomal Entry Site-Driven Translation

Chen

Kung

Weng

et al. 2013

J Virol

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Far-upstream element-binding protein 2 (FBP2) is an internal ribosomal entry site (IRES) trans-acting factor (ITAF) that negatively regulates enterovirus 71 (EV71) translation. This study shows that EV71 infection cleaved FBP2. Live EV71 and the EV71 replicon (but not UV-inactivated virus particles) induced FBP2 cleavage, suggesting that viral replication results in FBP2 cleavage. The results also showed that virus-induced proteasome, autophagy, and caspase activity co-contribute to EV71-induced FBP2 cleavage. Using FLAG-fused FBP2, we mapped the potential cleavage fragments of FBP2 in infected cells. We also found that FBP2 altered its function when its carboxyl terminus was cleaved. This study presents a mechanism for virus-induced cellular events to cleave a negative regulator for viral IRES-driven translation. Enterovirus 71 (EV71), an RNA virus that belongs to the family Picornaviridae, has caused several outbreaks worldwide and often results in severe neurological complications and high mortality in patients (1-10). Picornavirus infection can affect host mechanisms, such as host cap-dependent translation (11, 12), transcription (13,14), and immune responses (15-17). FBP2, also called the KH-type splicing regulatory protein (KSRP), was first identified as a single-strand DNA-binding protein (37). FBP2 positively regulates c-myc transcription (37), enhances the splicing of the neuron-specific c-src N1 exon (38, 39), edits apolipoprotein B (apoB) mRNA (40), and is associated with mRNA decay (41,42). FBP2 is also a component of the Dicer and Drosha complexes and regulates let-7 microRNA (miRNA) biogenesis (43-45). A previous study has shown that FBP2 binds to the EV71 5= untranslated region (UTR), which contains an IRES, and downregulates IRES activity by competing with other, positive ITAFs, such as PTB (35).In this study, we show that FBP2, a negative ITAF of EV71, is cleaved in EV71-infected cells. We also demonstrate that EV71-induced caspase activity, autophagic activity, and proteasome activity are involved in virus-induced cleavage of FBP2. Moreover, we found a cleavage product, FBP2 , that loses its carboxyl terminus and positively regulates the IRES activity of EV71. MATERIALS AND METHODS Cell lines and virus infection.Human embryonal rhabdomyosarcoma (RD) and HeLa cells were maintained in Dulbecco's modified Eagle medium (DMEM) (GIBCO) containing 10% fetal bovine serum (FBS; GIBCO) at 37°C. RD cells were grown to 80% to 90% confluence and were infected with enterovirus 71 strain Tainan/4643/98 at a multiplicity of infection (MOI) of 40 PFU per cell in serum-free DMEM. Virus was adsorbed at 37°C for 1 h. After adsorption, the cells were washed with phosphate-buffered saline (PBS) and were incubated with a medium containing 2% FBS. In several experiments, RD cells were infected with EV71 for 1 h, washed with PBS, and incubated with a medium containing 2% FBS and various inhibitors. UV-inactivated EV71 was prepared by following a method described elsewhere (46). In other experiments, RD cells were tran...

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Cleavage of IPS-1 in Cells Infected with Human Rhinovirus

Cited by 79 publications

References 37 publications

Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage

Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage

Coxsackievirus counters the host innate immune response by blocking type III interferon expression

Enterovirus 71 Infection Cleaves a Negative Regulator for Viral Internal Ribosomal Entry Site-Driven Translation

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