کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1963743 1058496 2010 12 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
AMPK-independent induction of autophagy by cytosolic Ca2+ increase
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
AMPK-independent induction of autophagy by cytosolic Ca2+ increase
چکیده انگلیسی
Autophagy is a eukaryotic lysosomal bulk degradation system initiated by cytosolic cargo sequestration in autophagosomes. The Ser/Thr kinase mTOR has been shown to constitute a central role in controlling the initiation of autophagy by integrating multiple nutrient-dependent signaling pathways that crucially involves the activity of PI3K class III to generate the phosphoinositide PI(3)P. Recent reports demonstrate that the increase in cytosolic Ca2+ can induce autophagy by inhibition of mTOR via the CaMKK-α/β-mediated activation of AMPK. Here we demonstrate that Ca2+ signaling can additionally induce autophagy independently of the Ca2+-mediated activation of AMPK. First, by LC3-II protein monitoring in the absence or presence of lysosomal inhibitors we confirm that the elevation of cytosolic Ca2+ induces autophagosome generation and does not merely block autophagosome degradation. Further, we demonstrate that Ca2+-chelation strongly inhibits autophagy in human, mouse and chicken cells. Strikingly, we found that the PI(3)P-binding protein WIPI-1 (Atg18) responds to the increase of cytosolic Ca2+ by localizing to autophagosomal membranes (WIPI-1 puncta) and that Ca2+-chelation inhibits WIPI-1 puncta formation, although PI(3)P-generation is not generally affected by these Ca2+ flux modifications. Importantly, using AMPK-α1−/−α2−/− MEFs we show that thapsigargin application triggers autophagy in the absence of AMPK and does not involve complete mTOR inhibition, as detected by p70S6K phosphorylation. In addition, STO-609-mediated CaMKK-α/β inhibition decreased the level of thapsigargin-induced autophagy only in AMPK-positive cells. We suggest that apart from reported AMPK-dependent regulation of autophagic degradation, an AMPK-independent pathway triggers Ca2+-mediated autophagy, involving the PI(3)P-effector protein WIPI-1 and LC3.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cellular Signalling - Volume 22, Issue 6, June 2010, Pages 914-925
نویسندگان
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