Picornaviruses and Apoptosis: Subversion of Cell Death

Croft, Sarah; Walker, Erin J.; Ghildyal, Reena

doi:10.1128/mbio.01009-17

Cited by 37 publications

(39 citation statements)

References 98 publications

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“…A subset of 3Cpro-transfected cells also underwent apoptosis without ASC speck formation (Fig. 1F,right panel), which was in agreement with the well-established pro-apoptotic roles of 3Cpros ( 26, 27 ). Taken together, these results demonstrate that 3Cpros can trigger significant inflammasome activation and pyroptosis in immortalized human keratinocytes.…”

Section: Main Textsupporting

confidence: 86%

Direct cleavage of human NLRP1 by enteroviral 3C protease triggers inflammasome activation in airway epithelium

Robinson

Sen²,

Teo³

et al. 2020

Preprint

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Viruses pose a constant threat to human health. As a result our innate immune system has evolved multiple strategies to detect the presence of intracellular viral pathogen-associated molecular patterns (PAMPs). The full repertoire of human immune sensors and their PAMP ligands are not completely understood. Here we report that human NLRP1 senses and is activated by 3C proteases (3Cpros) of enteroviruses. Mechanistically, 3Cpros cleave human NLRP1 at a single site immediately after its primate-specific PYRIN domain, leading to oligomerization of its C-terminal fragment. Expression of 3Cpros in primary human cells cause NLRP1-dependent ASC oligomerization, pyroptotic cell death and IL-1 secretion. Consistent with our observation that NLRP1 is the predominant endogenous inflammasome sensor in human airway epithelium, we find that its genetic deletion, or that of ASC, abrogates IL-18 secretion from rhinovirus (HRV)-infected primary human bronchial epithelial cells. Our findings identify the first cognate PAMP ligand for human NLRP1 and assign a new function for the NLRP1 inflammasome in human antiviral immunity and airway inflammation. These results challenge the widely held notion that viral proteases largely serve to disable host immune sensing, and suggest that the human NLRP1 inflammasome may be a therapeutic target to treat inflammatory airway diseases including asthma.

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Section: Main Textsupporting

confidence: 86%

Direct cleavage of human NLRP1 by enteroviral 3C protease triggers inflammasome activation in airway epithelium

Robinson

Sen²,

Teo³

et al. 2020

Preprint

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“…Infection with enteroviruses, specifically poliovirus, has been shown to promote apoptosis, which can result in the degradation of cellular proteins by executioner caspases [ 49 – 52 ]. To determine if SFPQ cleavage resulted from apoptotic induction and subsequent targeting by caspases, HeLa cells were infected with HRV16 in the presence or absence of the cell-permeable pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone (zVAD-FMK) and lysates generated 0, 4, and 8 hours post-infection.…”

Section: Resultsmentioning

confidence: 99%

Exploitation of nuclear functions by human rhinovirus, a cytoplasmic RNA virus

et al. 2018

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Protein production, genomic RNA replication, and virion assembly during infection by picornaviruses like human rhinovirus and poliovirus take place in the cytoplasm of infected human cells, making them the quintessential cytoplasmic pathogens. However, a growing body of evidence suggests that picornavirus replication is promoted by a number of host proteins localized normally within the host cell nucleus. To systematically identify such nuclear proteins, we focused on those that appear to re-equilibrate from the nucleus to the cytoplasm during infection of HeLa cells with human rhinovirus via quantitative protein mass spectrometry. Our analysis revealed a highly selective re-equilibration of proteins with known mRNA splicing and transport-related functions over nuclear proteins of all other functional classes. The multifunctional splicing factor proline and glutamine rich (SFPQ) was identified as one such protein. We found that SFPQ is targeted for proteolysis within the nucleus by viral proteinase 3CD/3C, and a fragment of SFPQ was shown to migrate to the cytoplasm at mid-to-late times of infection. Cells knocked down for SFPQ expression showed significantly reduced rhinovirus titers, viral protein production, and viral RNA accumulation, consistent with SFPQ being a pro-viral factor. The SFPQ fragment that moved into the cytoplasm was able to bind rhinovirus RNA either directly or indirectly. We propose that the truncated form of SFPQ promotes viral RNA stability or replication, or virion morphogenesis. More broadly, our findings reveal dramatic changes in protein compartmentalization during human rhinovirus infection, allowing the virus to systematically hijack the functions of proteins not normally found at its cytoplasmic site of replication.

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“…Other possible mechanisms include bystander activation of autoreactive T-cell clones driven by virus-induced inflammation, and the secretion of proinflammatory cytokines [25]. Virusinduced apoptosis or necrosis are also possible, since EVs can infect and damage human β-cells in vitro [26,27]. These hypotheses are summarized in detail below.…”

Section: Role Of Evs In T1dmentioning

confidence: 99%

Developing a vaccine for type 1 diabetes by targeting coxsackievirus B

Hyöty

León²,

Knip

2018

Expert Review of Vaccines

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Introduction: Virus infections have long been considered as a possible cause of type 1 diabetes (T1D). One virus group, enteroviruses (EVs), has been studied extensively, and clinical development of a vaccine against T1D-associated EV types has started. Areas covered: Epidemiological studies have indicated an association between EVs and T1D. These viruses have a strong tropism for insulin-producing β-cells; the destruction of these cells leads to T1D. The exact mechanisms by which EVs could cause T1D are not known, but direct infection of β-cells and virus-induced inflammation may play a role. Recent studies have narrowed down the epidemiological association to a subset of EVs: group B coxsackieviruses (CVBs). These findings have prompted efforts to develop vaccines against CVBs. Prototype CVB vaccines have prevented both infection and CVB-induced diabetes in mice. This review summarizes recent progress in the field and the specifics of what could constitute the first human vaccine developed for a chronic autoimmune disease. Expert commentary: Manufacturing of a clinical CVB vaccine as well as preclinical studies are currently in progress in order to enable clinical testing of the first CVB vaccine. Ongoing scientific research projects can significantly facilitate this effort by providing insights into the mechanisms of the CVB-T1D association.

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Picornaviruses and Apoptosis: Subversion of Cell Death

Cited by 37 publications

References 98 publications

Direct cleavage of human NLRP1 by enteroviral 3C protease triggers inflammasome activation in airway epithelium

Direct cleavage of human NLRP1 by enteroviral 3C protease triggers inflammasome activation in airway epithelium

Exploitation of nuclear functions by human rhinovirus, a cytoplasmic RNA virus

Developing a vaccine for type 1 diabetes by targeting coxsackievirus B

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