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Caspase-mediated cleavage of murine norovirus NS1/2 potentiates apoptosis and is required for persistent infection of intestinal epithelial cells.
Robinson, Bridget A; Van Winkle, Jacob A; McCune, Broc T; Peters, A Mack; Nice, Timothy J.
Afiliação
  • Robinson BA; Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, United States of America.
  • Van Winkle JA; Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, United States of America.
  • McCune BT; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America.
  • Peters AM; Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, United States of America.
  • Nice TJ; Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, United States of America.
PLoS Pathog ; 15(7): e1007940, 2019 07.
Article em En | MEDLINE | ID: mdl-31329638
Human norovirus (HNoV) is the leading cause of acute gastroenteritis and is spread by fecal shedding that can often persist for weeks to months after the resolution of symptoms. Elimination of persistent viral reservoirs has the potential to prevent outbreaks. Similar to HNoV, murine norovirus (MNV) is spread by persistent shedding in the feces and provides a tractable model to study molecular mechanisms of enteric persistence. Previous studies have identified non-structural protein 1 (NS1) from the persistent MNV strain CR6 as critical for persistent infection in intestinal epithelial cells (IECs), but its mechanism of action remains unclear. We now find that the function of CR6 NS1 is regulated by apoptotic caspase cleavage. Following induction of apoptosis in infected cells, caspases cleave the precursor NS1/2 protein, and this cleavage is prevented by mutation of caspase target motifs. These mutations profoundly compromise CR6 infection of IECs and persistence in the intestine. Conversely, NS1/2 cleavage is not strictly required for acute replication in extra-intestinal tissues or in cultured myeloid cells, suggesting an IEC-centric role. Intriguingly, we find that caspase cleavage of CR6 NS1/2 reciprocally promotes caspase activity, potentiates cell death, and amplifies spread among cultured IEC monolayers. Together, these data indicate that the function of CR6 NS1 is regulated by apoptotic caspases, and suggest that apoptotic cell death enables epithelial spread and persistent shedding.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas não Estruturais Virais / Norovirus / Mucosa Intestinal Tipo de estudo: Etiology_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas não Estruturais Virais / Norovirus / Mucosa Intestinal Tipo de estudo: Etiology_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article