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Particle Agglutination Method for Poliovirus Identification
Published on: April 20, 2011
MDA-5 is cleaved in poliovirus-infected cells
Paola M Barral1, Juliet M Morrison, Jennifer Drahos
1Department of Urology, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians & Surgeons, 701 W. 168th St., New York, NY 10032, USA.
Abstract:
Infections with RNA viruses are sensed by the innate immune system through membrane-bound Toll-like receptors or the cytoplasmic RNA helicases RIG-I and MDA-5. It is believed that MDA-5 is crucial for sensing infections by picornaviruses, but there have been no studies on the role of this protein during infection with poliovirus, the prototypic picornavirus. Beginning at 4 h postinfection, MDA-5 protein is degraded in poliovirus-infected cells. Levels of MDA-5 declined beginning at 6 h after infection with rhinovirus type 1a or encephalomyocarditis virus, but the protein was stable in cells infected with rhinovirus type 16 or echovirus type 1. Cleavage of MDA-5 is not carried out by either poliovirus proteinase 2Apro or 3Cpro. Instead, degradation of MDA-5 in poliovirus-infected cells occurs in a proteasome- and caspase-dependent manner. Degradation of MDA-5 during poliovirus infection correlates with cleavage of poly(ADP) ribose polymerase (PARP), a hallmark of apoptosis. Induction of apoptosis by puromycin leads to cleavage of both PARP and MDA-5. The MDA-5 cleavage product observed in cells treated with puromycin is approximately 90 kDa, similar in size to the putative cleavage product observed in poliovirus-infected cells. Poliovirus-induced cleavage of MDA-5 may be a mechanism to antagonize production of type I interferon in response to viral infection.
Insights
Poliovirus infection triggers the degradation of MDA-5, a key sensor of viral RNA. This degradation, occurring via proteasome and caspase pathways, may help the virus evade the innate immune response.
Area of Science:
- * Immunology
- * Virology
- * Molecular Biology
Background:
- * The innate immune system detects RNA viruses using Toll-like receptors (TLRs) and RNA helicases like RIG-I and MDA-5.
- * MDA-5 is thought to be vital for sensing picornavirus infections, but its role in poliovirus infection was unstudied.
- * Picornaviruses, including poliovirus, are significant human pathogens.
Purpose of the Study:
- * To investigate the role and fate of MDA-5 during poliovirus infection.
- * To determine the mechanism of MDA-5 degradation in infected cells.
- * To explore the implications of MDA-5 degradation for antiviral responses.
Main Methods:
- * Western blot analysis to detect MDA-5 protein levels in infected cells.
- * Infection of cells with various picornaviruses (poliovirus, rhinovirus, encephalomyocarditis virus, echovirus).
- * Treatment of cells with proteasome and caspase inhibitors.
- * Induction of apoptosis using puromycin and analysis of protein cleavage.
Main Results:
- * MDA-5 protein levels significantly declined in poliovirus-infected cells starting at 4 hours post-infection.
- * MDA-5 degradation was observed with other picornaviruses (rhinovirus type 1a, encephalomyocarditis virus) but not all (rhinovirus type 16, echovirus type 1).
- * Poliovirus proteinase 2Apro or 3Cpro did not directly cleave MDA-5; degradation required proteasome and caspase activity.
- * MDA-5 degradation correlated with poly(ADP) ribose polymerase (PARP) cleavage, a marker of apoptosis.
- * Puromycin-induced apoptosis resulted in cleavage of both PARP and MDA-5, producing a ~90 kDa fragment similar to that seen in poliovirus infection.
Conclusions:
- * Poliovirus infection leads to the degradation of the innate immune sensor MDA-5 through proteasome- and caspase-dependent pathways.
- * This degradation is linked to apoptosis induction and is not mediated by viral proteases.
- * Poliovirus-induced MDA-5 cleavage may represent a viral strategy to antagonize the type I interferon response, thereby promoting viral replication.
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