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SARS-Coronavirus Open Reading Frame-3a drives multimodal necrotic cell death
- Source :
- Cell Death & Disease, Cell Death and Disease, Vol 9, Iss 9, Pp 1-15 (2018)
- Publication Year :
- 2018
- Publisher :
- Springer Science and Business Media LLC, 2018.
-
Abstract
- The molecular mechanisms underlying the severe lung pathology that occurs during SARS-CoV infections remain incompletely understood. The largest of the SARS-CoV accessory protein open reading frames (SARS 3a) oligomerizes, dynamically inserting into late endosomal, lysosomal, and trans-Golgi-network membranes. While previously implicated in a non-inflammatory apoptotic cell death pathway, here we extend the range of SARS 3a pathophysiologic targets by examining its effects on necrotic cell death pathways. We show that SARS 3a interacts with Receptor Interacting Protein 3 (Rip3), which augments the oligomerization of SARS 3a helping drive necrotic cell death. In addition, by inserting into lysosomal membranes SARS 3a triggers lysosomal damage and dysfunction. Consequently, Transcription Factor EB (TFEB) translocates to the nucleus increasing the transcription of autophagy- and lysosome-related genes. Finally, SARS 3a activates caspase-1 either directly or via an enhanced potassium efflux, which triggers NLRP3 inflammasome assembly. In summary, Rip3-mediated oligomerization of SARS 3a causes necrotic cell death, lysosomal damage, and caspase-1 activation—all likely contributing to the clinical manifestations of SARS-CoV infection.
- Subjects :
- 0301 basic medicine
Cancer Research
Endosome
Inflammasomes
Immunology
Apoptosis
Biology
Severe Acute Respiratory Syndrome
Article
Cell Line
03 medical and health sciences
Cellular and Molecular Neuroscience
Necrosis
Open Reading Frames
Cell Line, Tumor
medicine
Autophagy
Humans
lcsh:QH573-671
skin and connective tissue diseases
A549 cell
lcsh:Cytology
HEK 293 cells
fungi
Inflammasome
Cell Biology
Intracellular Membranes
Cell biology
body regions
Open reading frame
030104 developmental biology
HEK293 Cells
Severe acute respiratory syndrome-related coronavirus
Cell culture
A549 Cells
Receptor-Interacting Protein Serine-Threonine Kinases
TFEB
Lysosomes
medicine.drug
HeLa Cells
Subjects
Details
- ISSN :
- 20414889
- Volume :
- 9
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Cell Death & Disease
- Accession number :
- edsair.doi.dedup.....8e0cb4ab81aeb23953246b1d4d605265
- Full Text :
- https://doi.org/10.1038/s41419-018-0917-y