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Virology. 2014 Mar;452-453:175-90. doi: 10.1016/j.virol.2014.01.008. Epub 2014 Feb 5.
mTOR/p70S6K signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza A infection.
Datan E1, Shirazian A1, Benjamin S1, Matassov D1, Tinari A2, Malorni W3, Lockshin RA1, Garcia-Sastre A4, Zakeri Z5.
Author information
Abstract
Autophagy, a stress response activated in influenza A virus infection helps the cell avoid apoptosis. However, in the absence of apoptosis infected cells undergo vastly expanded autophagy and nevertheless die in the presence of necrostatin but not of autophagy inhibitors. Combinations of inhibitors indicate that the controls of protective and lethal autophagy are different. Infection that triggers apoptosis also triggers canonical autophagy signaling exhibiting transient PI3K and mTORC1 activity. In terminal autophagy phospho-mTOR(Ser2448) is suppressed while mTORC1, PI3K and mTORC2 activities increase. mTORC1 substrate p70S6K becomes highly phosphorylated while its activity, now regulated by mTORC2, is required for LC3-II formation. Inhibition of mTORC2/p70S6K, unlike that of PI3K/mTORC1, blocks expanded autophagy in the absence of apoptosis but not moderate autophagy. Inhibitors of expanded autophagy limit virus reproduction. Thus expanded, lethal autophagy is activated by a signaling mechanism different from autophagy that helps cells survive toxic or stressful episodes.
Copyright ? 2014 Elsevier Inc. All rights reserved.
KEYWORDS:
Apoptosis, Autophagy, Cell death, Influenza, Rapamycin, Torin1, mTORC1/2, p70S6K
PMID:
24606695
[PubMed - in process]
mTOR/p70S6K signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza A infection.
Datan E1, Shirazian A1, Benjamin S1, Matassov D1, Tinari A2, Malorni W3, Lockshin RA1, Garcia-Sastre A4, Zakeri Z5.
Author information
Abstract
Autophagy, a stress response activated in influenza A virus infection helps the cell avoid apoptosis. However, in the absence of apoptosis infected cells undergo vastly expanded autophagy and nevertheless die in the presence of necrostatin but not of autophagy inhibitors. Combinations of inhibitors indicate that the controls of protective and lethal autophagy are different. Infection that triggers apoptosis also triggers canonical autophagy signaling exhibiting transient PI3K and mTORC1 activity. In terminal autophagy phospho-mTOR(Ser2448) is suppressed while mTORC1, PI3K and mTORC2 activities increase. mTORC1 substrate p70S6K becomes highly phosphorylated while its activity, now regulated by mTORC2, is required for LC3-II formation. Inhibition of mTORC2/p70S6K, unlike that of PI3K/mTORC1, blocks expanded autophagy in the absence of apoptosis but not moderate autophagy. Inhibitors of expanded autophagy limit virus reproduction. Thus expanded, lethal autophagy is activated by a signaling mechanism different from autophagy that helps cells survive toxic or stressful episodes.
Copyright ? 2014 Elsevier Inc. All rights reserved.
KEYWORDS:
Apoptosis, Autophagy, Cell death, Influenza, Rapamycin, Torin1, mTORC1/2, p70S6K
PMID:
24606695
[PubMed - in process]
