PubMed Journals: Cell Death Discov
Source: PMID: 31231549⇦⇨ Cell Death Discov. 2019 Jun 5;5:101. doi:
⇩10.1038/s41420-019-0181-7. eCollection 2019.
SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress
pathways and activates NLRP3 inflammasomes.
Shi CS(1), Nabar NR(1), Huang NN(1), Kehrl
(1) B Cell Molecular Immunology Section,
Laboratory of Immunoregulation, National
Institute of Allergy and Infectious Diseases,
National Institutes of Health, Bethesda,
MD 20892 USA.
The SARS (severe acute respiratory syndrome)
outbreak was caused by a coronavirus (CoV)
named the SARS-CoV. SARS pathology is propagated
both by direct cytotoxic effects of the
virus and aberrant activation of the innate
immune response. Here, we identify several
mechanisms by which a SARS-CoV open reading
frame (ORF) activates intracellular stress pathways
and targets the innate immune response.
We show that ORF8b forms insoluble intracellular
aggregates dependent on a valine at residue 77.
Aggregated ORF8b induces endoplasmic reticulum
(ER) stress, lysosomal damage, and subsequent
activation of the master regulator of the
autophagy and lysosome machinery,
Transcription factor EB (TFEB). ORF8b causes
cell death in epithelial cells, which is
partially rescued by reducing its ability
to aggregate. In macrophages, ORF8b robustly
activates the NLRP3 inflammasome by providing
a potent signal 2 required for activation.
Mechanistically, ORF8b interacts directly
with the Leucine Rich Repeat domain of NLRP3
and localizes with NLRP3 and ASC in cytosolic
dot-like structures. ORF8b triggers cell
death consistent with pyroptotic cell death in
macrophages. While in those cells lacking
NLRP3 accumulating ORF8b cytosolic aggregates cause
ER stress, mitochondrial dysfunction, and
caspase-independent cell death.
DOI: 10.1038/s41420-019-0181-7PMCID: PMC6549181PMID: 31231549
Conflict of interest statement: Conflict
of interestThe authors declare that they
have no conflict of interest.