BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-XL
BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-XL
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DOI：
10.4161/auto.4237
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发表时间：
2007-07-01
期刊：
影响因子：
13.3
通讯作者：
Kroemer, Guido
中科院分区：
文献类型：
--
作者：
Maiuri, Maria Chiara;Criollo, Alfredo;Kroemer, Guido
Beclin 1最近被鉴定为新的仅BH 3蛋白，这意味着它携带一个Bcl-2同源性-3（BH 3）结构域。作为其他仅BH 3蛋白，Beclin 1凭借其BH 3结构域（结合Bcl-2/Bcl-X-L的疏水裂缝的两亲性α-螺旋）与Bcl-2家族的抗凋亡多结构域蛋白（特别是Bcl-2及其同源物Bcl-X-L）相互作用。其他仅含BH 3的蛋白如Bad的BH 3结构域以及BH 3模拟化合物如ABT 737竞争性地破坏Beclin 1和Bcl-2/Bcl-X-L之间的抑制性相互作用。这引起线粒体的自噬（线粒体自噬），但不引起内质网的自噬（网状吞噬）。只有ER靶向的（非Bclon靶向的）Bcl-2/Bcl-X-L可以抑制Beclin 1诱导的自噬，并且只有存在于ER中的Beclin 1-Bcl-2/Bcl-X-L复合物（而不是存在于线粒体中富集的重膜部分上的那些复合物）被ABT 737破坏。这些研究结果表明，Beclin 1-Bcl-2/Bcl-X-L复合物，通常抑制自噬是专门位于ER和点的细胞器特异性调节自噬。此外，这些数据表明，空间组织的自噬和凋亡控制，其中BH 3-唯一的蛋白发挥两个独立的功能。一方面，它们可以通过（直接或间接地）激活来自Bcl-2家族的促凋亡多结构域蛋白的细胞膜透化功能来诱导凋亡。另一方面，它们可以通过在内质网水平将Beclin 1从Bcl-2/Bcl-X-L的抑制中释放出来来激活自噬。
Beclin 1 has recently been identified as novel BH3-only protein, meaning that it carries one Bcl-2-homology-3 (BH3) domain. As other BH3-only proteins, Beclin 1 interacts with anti-apoptotic multidomain proteins of the Bcl-2 family (in particular Bcl-2 and its homologue Bcl-X-L) by virtue of its BH3 domain, an amphipathic a-helix that binds to the hydrophobic cleft of Bcl-2/Bcl-X-L. The BH3 domains of other BH3-only proteins such as Bad, as well as BH3-mimetic compounds such as ABT737, competitively disrupt the inhibitory interaction between Beclin 1 and Bcl-2/Bcl-X-L. This causes autophagy of mitochondria (mitophagy) but not of the endoplasmic reticulum (reticulophagy). Only ER-targeted (not mitochondrion-targeted) Bcl-2/Bcl-X-L can inhibit autophagy induced by Beclin 1, and only Beclin 1-Bcl-2/Bcl-X-L complexes present in the ER (but not those present on heavy membrane fractions enriched in mitochondria) are disrupted by ABT737. These findings suggest that the Beclin 1-Bcl-2/Bcl-X-L complexes that normally inhibit autophagy are specifically located in the ER and point to an organelle-specific regulation of autophagy. Furthermore, these data suggest a spatial organization of autophagy and apoptosis control in which BH3-only proteins exert two independent functions. On the one hand, they can induce apoptosis, by (directly or indirectly) activating the mitochondrion-permeabilizing function of pro-apoptotic multidomain proteins from the Bcl-2 family. On the other hand, they can activate autophagy by liberating Beclin 1 from its inhibition by Bcl-2/Bcl-X-L at the level of the endoplasmic reticulum.