Cardiovirus Leader proteins bind exportins: Implications for virus replication and nucleocytoplasmic trafficking inhibition

Ciomperlik, Jessica J.; Basta, Holly A.; Palmenberg, Ann C.

doi:10.1016/j.virol.2015.10.001

Cited by 8 publications

(9 citation statements)

References 23 publications

(68 reference statements)

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“…TMEV inhibits the production of IFN-I by blocking the nuclear translocation of IRF3 with its L protein [123,124]. The inhibition of nucleocytoplasmic trafficking is caused by L protein-exportin interactions and subsequent phosphorylation of Phe/Gly-containing nuclear pore proteins (Nup62 and Nup98) [125,126]. Furthermore, persistent TO strains express an additional protein called L* protein via an alternative open reading frame (ORF) in the regions of L, VP4, and VP2, which inhibit the IFN-I inducible oligoadenylate synthetases (OAS)/RNase L pathway that cleaves viral and cellular RNA [127,128].…”

Section: Innate Immunity In Theiler’s Murine Encephalomyelitis Virmentioning

confidence: 99%

“…In TMEV-DA-infected mice, IL1β does not seem to play a major role in seizures because IL1 receptor I- and MyD88-deficient C57BL/6 mice have a seizure frequency similar to wild type mice. In contrast, only 10% of TNF receptor I- and 15% of IL6-deficient C57BL/6 mice showed signs of seizure activity, and fewer seizures are seen in TNFα −/− mice bred on a C57BL/6 background [98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,…”

Section: Innate Immunity In Theiler’s Murine Encephalomyelitis Virmentioning

confidence: 99%

See 1 more Smart Citation

Facets of Theiler’s Murine Encephalomyelitis Virus-Induced Diseases: An Update

Gerhauser

Hansmann

Ciurkiewicz

et al. 2019

IJMS

104

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Theiler’s murine encephalomyelitis virus (TMEV), a naturally occurring, enteric pathogen of mice is a Cardiovirus of the Picornaviridae family. Low neurovirulent TMEV strains such as BeAn cause a severe demyelinating disease in susceptible SJL mice following intracerebral infection. Furthermore, TMEV infections of C57BL/6 mice cause acute polioencephalitis initiating a process of epileptogenesis that results in spontaneous recurrent epileptic seizures in approximately 50% of affected mice. Moreover, C3H mice develop cardiac lesions after an intraperitoneal high-dose application of TMEV. Consequently, TMEV-induced diseases are widely used as animal models for multiple sclerosis, epilepsy, and myocarditis. The present review summarizes morphological lesions and pathogenic mechanisms triggered by TMEV with a special focus on the development of hippocampal degeneration and seizures in C57BL/6 mice as well as demyelination in the spinal cord in SJL mice. Furthermore, a detailed description of innate and adaptive immune responses is given. TMEV studies provide novel insights into the complexity of organ- and mouse strain-specific immunopathology and help to identify factors critical for virus persistence.

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Section: Innate Immunity In Theiler’s Murine Encephalomyelitis Virmentioning

confidence: 99%

Section: Innate Immunity In Theiler’s Murine Encephalomyelitis Virmentioning

confidence: 99%

Facets of Theiler’s Murine Encephalomyelitis Virus-Induced Diseases: An Update

Gerhauser

Hansmann

Ciurkiewicz

et al. 2019

IJMS

104

View full text Add to dashboard Cite

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“…Upon nuclear localization, L interacts with Ran with high affinity and 2A is displaced as the binding sites for 2A and Ran partially overlap ( Petty et al, 2014 ). L from EMCV, TMEV, and SAFV induce hyper-phosphorylation of Nups including Nup62 and Nup98 ( Ricour et al, 2009 ; Ciomperlik et al, 2015 ), likely by recruiting and activating a kinase, which may be facilitated by L binding of exportins Crm1 and CAS ( Ciomperlik et al, 2016 ). Chemical inhibition of ERK and p38 was able to block L-mediated hyper-phosphorylation of Nups ( Porter et al, 2010 ).…”

Section: Inhibition Of Interferon Production By Cardiovirusesmentioning

confidence: 99%

Innate Immune Detection of Cardioviruses and Viral Disruption of Interferon Signaling

2018

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Cardioviruses are members of the Picornaviridae family and infect a variety of mammals, from mice to humans. Replication of cardioviruses produces double stranded RNA that is detected by helicases in the RIG-I-like receptor family and leads to a signaling cascade to produce type I interferon. Like other viruses within Picornaviridae, however, cardioviruses have evolved several mechanisms to inhibit interferon production. In this review, we summarize recent findings that have uncovered several proteins enabling efficient detection of cardiovirus dsRNA and discuss which cell types may be most important for interferon production in vivo. Additionally, we describe how cardiovirus proteins L, 3C and L∗ disrupt interferon production and antagonize the antiviral activity of interferon effector molecules.

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“…TDP-43 proteinopathy has been described in a number of diseases in addition to ALS [11]. Since the leader (L) protein of Theiler’s murine encephalomyelitis virus (TMEV), a member of the Cardiovirus genus of Picornaviridae , is known to disrupt nucleocytoplasmic transport [12, 13], we wondered whether TDP-43 proteinopathy occurs in infections with this pathogen; however, it is known that different RNA binding proteins and different protein compositions of the nuclear pore complex are present in different cell types [14]. TMEV includes strains of two subgroups with different disease phenotypes in mice [15].…”

Section: Introductionmentioning

confidence: 99%

TDP-43 proteinopathy in Theiler’s murine encephalomyelitis virus infection

et al. 2019

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TDP-43, an RNA-binding protein that is primarily nuclear and important in splicing and RNA metabolism, is mislocalized from the nucleus to the cytoplasm of neural cells in amyotrophic lateral sclerosis (ALS), and contributes to disease. We sought to investigate whether TDP-43 is mislocalized in infections with the acute neuronal GDVII strain and the persistent demyelinating DA strain of Theiler’s virus murine encephalomyelitis virus (TMEV), a member of the Cardiovirus genus of Picornaviridae because: i) L protein of both strains is known to disrupt nucleocytoplasmic transport, including transport of polypyrimidine tract binding protein, an RNA-binding protein, ii) motor neurons and oligodendrocytes are targeted in both TMEV infection and ALS. TDP-43 phosphorylation, cleavage, and cytoplasmic mislocalization to an aggresome were observed in wild type TMEV-infected cultured cells, with predicted splicing abnormalities. In contrast, cells infected with DA and GDVII strains that have L deletion had rare TDP-43 mislocalization and no aggresome formation. TDP-43 mislocalization was also present in neural cells of TMEV acutely-infected mice. Of note, TDP-43 was mislocalized six weeks after DA infection to the cytoplasm of oligodendrocytes and other glial cells in demyelinating lesions of spinal white matter. A recent study showed that TDP-43 knock down in oligodendrocytes in mice led to demyelination and death of this neural cell [ 1 ], suggesting that TMEV infection mislocalization of TDP-43 and other RNA-binding proteins is predicted to disrupt key cellular processes and contribute to the pathogenesis of TMEV-induced diseases. Drugs that inhibit nuclear export may have a role in antiviral therapy.

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Cardiovirus Leader proteins bind exportins: Implications for virus replication and nucleocytoplasmic trafficking inhibition

Cited by 8 publications

References 23 publications

Facets of Theiler’s Murine Encephalomyelitis Virus-Induced Diseases: An Update

Facets of Theiler’s Murine Encephalomyelitis Virus-Induced Diseases: An Update

Innate Immune Detection of Cardioviruses and Viral Disruption of Interferon Signaling

TDP-43 proteinopathy in Theiler’s murine encephalomyelitis virus infection

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