Regulation of autophagy by the inositol trisphosphate receptor
Regulation of autophagy by the inositol trisphosphate receptor
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DOI：
10.1038/sj.cdd.4402099
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发表时间：
2007-05-01
影响因子：
12.4
通讯作者：
Kroemer, G.
中科院分区：
文献类型：
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作者：
Criollo, A.;Maiuri, M. C.;Kroemer, G.
细胞内1，4，5-三磷酸肌醇（IP 3）水平的降低刺激自噬，而IP 3水平的提高抑制由营养耗尽诱导的自噬。在这里，我们表明，敲低IP 3受体（IP 3R）与小干扰RNA和药理学IP 3R封锁是一个强大的刺激诱导自噬。已知IP 3R存在于内质网（ER）的膜中以及ER -线粒体接触位点内，并且IP 3R阻断触发ER和线粒体两者的自噬，如在饥饿诱导的自噬中确切观察到的。ER应激因子如衣霉素和毒胡萝卜素也诱导ER的自噬，并且在较小程度上诱导线粒体的自噬。由饥饿或IP 3R阻断引发的自噬被特异性靶向ER的Bcl-2和Bcl-XL抑制，但不被靶向线粒体的Bcl-2或Bcl-XL蛋白抑制。相反，内质网应激诱导的自噬不被Bcl-2和Bcl- XL抑制. IP 3R抑制促进的自噬不能归因于ER或胞质溶胶中稳态Ca 2+水平的调节，但涉及Beclin-1、自噬相关基因（Atg）5、Atg 10、Atg 12和hVps 34的专性贡献。总之，这些结果强烈表明，IP 3R发挥了重要作用的生理控制的自噬。
The reduction of intracellular 1,4,5- inositol trisphosphate ( IP3) levels stimulates autophagy, whereas the enhancement of IP3 levels inhibits autophagy induced by nutrient depletion. Here, we show that knockdown of the IP3 receptor ( IP3R) with small interfering RNAs and pharmacological IP3R blockade is a strong stimulus for the induction of autophagy. The IP3R is known to reside in the membranes of the endoplasmic reticulum ( ER) as well as within ER - mitochondrial contact sites, and IP3R blockade triggered the autophagy of both ER and mitochondria, as exactly observed in starvation- induced autophagy. ER stressors such as tunicamycin and thapsigargin also induced autophagy of ER and, to less extent, of mitochondria. Autophagy triggered by starvation or IP3R blockade was inhibited by Bcl-2 and Bcl-XL specifically targeted to ER but not Bcl-2 or Bcl-XL proteins targeted to mitochondria. In contrast, ER stress- induced autophagy was not inhibited by Bcl-2 and Bcl- XL. Autophagy promoted by IP3R inhibition could not be attributed to a modulation of steady- state Ca2+ levels in the ER or in the cytosol, yet involved the obligate contribution of Beclin-1, autophagy- related gene (Atg) 5, Atg10, Atg12 and hVps34. Altogether, these results strongly suggest that IP3R exerts a major role in the physiological control of autophagy.