The VDAC2-BAK axis regulates peroxisomal membrane permeability.
The VDAC2-BAK axis regulates peroxisomal membrane permeability.
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DOI：
10.1083/jcb.201605002
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发表时间：
2017-03-06
期刊：
影响因子：
--
通讯作者：
Fujiki Y
中科院分区：
文献类型：
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作者：
Hosoi KI;Miyata N;Mukai S;Furuki S;Okumoto K;Cheng EH;Fujiki Y
VDAC2控制BAK对线粒体的稳定定位及其介导线粒体外膜渗透的能力。Hosoi等人现在报道，在vdac2缺乏的情况下，BAK从线粒体转移到过氧化物酶体，导致过氧化氢酶等过氧化物酶体基质蛋白错定位，这表明BAK也可以调节过氧化物酶体膜的通透性。过氧化物酶体生物发生障碍（PBDs）是由14个互补基团（CGs）组成的致命性遗传病。我们之前分离了一个过氧化物酶体缺陷的中国仓鼠卵巢细胞突变体ZP114，它不属于这些基因。使用功能筛选策略，VDAC2被鉴定为挽救了未检测到VDAC2表达的ZP114过氧化物酶体缺陷。有趣的是，敲除BAK或过表达BAK抑制剂BCL-XL和MCL-1可恢复ZP114细胞中过氧化物酶体的生物发生。虽然VDAC2不定位于过氧化物酶体，但VDAC2的缺失会使BAK的定位从线粒体转移到过氧化物酶体，从而导致过氧化物酶体缺陷。将携带Pex26p跨膜区域的过氧化物酶体靶向BAK引入野生型细胞，导致过氧化物酶体基质蛋白释放到细胞质中。此外，BAK激活因子PUMA和BIM的过表达以依赖BAK的方式使过氧化物酶体渗透。总的来说，这些发现表明BAK在过氧化物酶体通透性中起作用，类似于线粒体外膜通透性。
VDAC2 controls the stable localization of BAK to mitochondria and its ability to mediate mitochondrial outer membrane permeabilization. Hosoi et al. now report that BAK shifts from mitochondria to peroxisomes under VDAC2-deficient conditions, giving rise to the mislocalization of peroxisomal matrix proteins such as catalase, which suggests that BAK can also regulate the permeability of peroxisomal membranes. Peroxisomal biogenesis disorders (PBDs) are fatal genetic diseases consisting of 14 complementation groups (CGs). We previously isolated a peroxisome-deficient Chinese hamster ovary cell mutant, ZP114, which belongs to none of these CGs. Using a functional screening strategy, VDAC2 was identified as rescuing the peroxisomal deficiency of ZP114 where VDAC2 expression was not detected. Interestingly, knockdown of BAK or overexpression of the BAK inhibitors BCL-XL and MCL-1 restored peroxisomal biogenesis in ZP114 cells. Although VDAC2 is not localized to the peroxisome, loss of VDAC2 shifts the localization of BAK from mitochondria to peroxisomes, resulting in peroxisomal deficiency. Introduction of peroxisome-targeted BAK harboring the Pex26p transmembrane region into wild-type cells resulted in the release of peroxisomal matrix proteins to cytosol. Moreover, overexpression of BAK activators PUMA and BIM permeabilized peroxisomes in a BAK-dependent manner. Collectively, these findings suggest that BAK plays a role in peroxisomal permeability, similar to mitochondrial outer membrane permeabilization.