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

			Author Information
			(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/s41420-019-0181-7 PMCID: PMC6549181
			PMID: 31231549

			Conflict of interest statement: Conflict
			of interestThe authors declare that they
			have no conflict of interest.

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