PMID- 31329638
OWN - NLM
STAT- MEDLINE
DCOM- 20200102
LR  - 20210113
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 15
IP  - 7
DP  - 2019 Jul
TI  - Caspase-mediated cleavage of murine norovirus NS1/2 potentiates apoptosis and is 
      required for persistent infection of intestinal epithelial cells.
PG  - e1007940
LID - 10.1371/journal.ppat.1007940 [doi]
LID - e1007940
AB  - 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.
FAU - Robinson, Bridget A
AU  - Robinson BA
AUID- ORCID: 0000-0002-3332-9510
AD  - Department of Molecular Microbiology and Immunology, Oregon Health and Science 
      University, Portland, Oregon, United States of America.
FAU - Van Winkle, Jacob A
AU  - Van Winkle JA
AUID- ORCID: 0000-0002-4422-4175
AD  - Department of Molecular Microbiology and Immunology, Oregon Health and Science 
      University, Portland, Oregon, United States of America.
FAU - McCune, Broc T
AU  - McCune BT
AUID- ORCID: 0000-0002-8342-5316
AD  - Department of Microbiology, University of Texas Southwestern Medical Center, 
      Dallas, TX, United States of America.
FAU - Peters, A Mack
AU  - Peters AM
AD  - Department of Molecular Microbiology and Immunology, Oregon Health and Science 
      University, Portland, Oregon, United States of America.
FAU - Nice, Timothy J
AU  - Nice TJ
AUID- ORCID: 0000-0002-4471-7666
AD  - Department of Molecular Microbiology and Immunology, Oregon Health and Science 
      University, Portland, Oregon, United States of America.
LA  - eng
GR  - R01 AI130055/AI/NIAID NIH HHS/United States
GR  - T32 AI007472/AI/NIAID NIH HHS/United States
GR  - T32 GM071338/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190722
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (Viral Nonstructural Proteins)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Caliciviridae Infections/etiology/pathology/virology
MH  - Caspases/metabolism
MH  - Cells, Cultured
MH  - Epithelial Cells/metabolism/pathology/virology
MH  - Female
MH  - Gastroenteritis/etiology/pathology/virology
MH  - Host Microbial Interactions
MH  - Humans
MH  - Intestinal Mucosa/metabolism/pathology/*virology
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Models, Biological
MH  - Myeloid Cells/metabolism/pathology/virology
MH  - Norovirus/genetics/*pathogenicity/physiology
MH  - Viral Nonstructural Proteins/genetics/*metabolism
MH  - Virus Replication
MH  - Virus Shedding
PMC - PMC6675124
COIS- The authors have declared that no competing interests exist.
EDAT- 2019/07/23 06:00
MHDA- 2020/01/03 06:00
PMCR- 2019/07/22
CRDT- 2019/07/23 06:00
PHST- 2019/03/26 00:00 [received]
PHST- 2019/06/24 00:00 [accepted]
PHST- 2019/08/01 00:00 [revised]
PHST- 2019/07/23 06:00 [pubmed]
PHST- 2020/01/03 06:00 [medline]
PHST- 2019/07/23 06:00 [entrez]
PHST- 2019/07/22 00:00 [pmc-release]
AID - PPATHOGENS-D-19-00575 [pii]
AID - 10.1371/journal.ppat.1007940 [doi]
PST - epublish
SO  - PLoS Pathog. 2019 Jul 22;15(7):e1007940. doi: 10.1371/journal.ppat.1007940. 
      eCollection 2019 Jul.