Abstract：
As a persistent organic pollutant, perfluorooctane sulfonate (PFOS) has a serious detrimental impact on human health. It has been suggested that PFOS is associated with liver inflammation. However, the underlying mechanisms are still unclear. Here, PFOS was found to elevate the oligomerization tendency of voltage-dependent anion channel 1 (VDAC1) in the mice liver and human normal liver cells L-02. Inhibition of VDAC1 oligomerization alleviated PFOS-induced nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome activation. Cytoplasmic membrane VDAC1 translocated to mitochondria was also observed in response to PFOS. Therefore, the oligomerization of VDAC1 occurred mainly in the mitochondria. VDAC1 was found to interact with the ATP synthase beta subunit (ATP5B) under PFOS treatment. Knockdown of ATP5B or immobilization of ATP5B to the cytoplasmic membrane alleviated the increased VDAC1 oligomerization and NLRP3 inflammasome activation. Therefore, our results suggested that PFOS induced NLRP3 inflammasome activation through VDAC1 oligomerization, a process dependent on ATP5B to transfer VDAC1 from the plasma membrane to the mitochondria. The findings offer novel perspectives on the activation of the NLRP3 inflammasome, the regulatory mode on VDAC1 oligomerization, and the mechanism of PFOS toxicity.
摘要：
作为一种持久性有机污染物,全氟辛烷磺酸（PFOS）对人类健康有严重的不利影响。有人认为全氟辛烷磺酸与肝脏炎症有关。然而,潜在机制尚不清楚.这里,发现全氟辛烷磺酸可提高小鼠肝脏和人正常肝细胞L-02中电压依赖性阴离子通道1（VDAC1）的寡聚化趋势。VDAC1寡聚化的抑制减轻了PFOS诱导的核苷酸结合域和富含亮氨酸的重复蛋白-3(NLRP3)炎性体激活。还观察到细胞质膜VDAC1对全氟辛烷磺酸的反应易位到线粒体。因此,VDAC1的寡聚化主要发生在线粒体中。在PFOS处理下，发现VDAC1与ATP合酶β亚基（ATP5B）相互作用。敲除ATP5B或将ATP5B固定到胞质膜减轻了增加的VDAC1寡聚化和NLRP3炎性体激活。因此,我们的结果表明，全氟辛烷磺酸通过VDAC1寡聚化诱导NLRP3炎性体激活，依赖于ATP5B将VDAC1从质膜转移到线粒体的过程。这些发现为NLRP3炎性体的激活提供了新的观点，VDAC1寡聚化的调控模式，以及全氟辛烷磺酸的毒性机制。
