BNIP3 upregulation via stimulation of ERK and JNK activity is required for the protection of keratinocytes from UVB-induced apoptosis.
BNIP3 upregulation via stimulation of ERK and JNK activity is required for the protection of keratinocytes from UVB-induced apoptosis.
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DOI：
10.1038/cddis.2017.4
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发表时间：
2017-02-02
影响因子：
9
通讯作者：
Hayakawa T
中科院分区：
文献类型：
--
作者：
Moriyama M;Moriyama H;Uda J;Kubo H;Nakajima Y;Goto A;Morita T;Hayakawa T
人体皮肤在屏障功能中具有重要作用。来自阳光照射的紫外线（UV）可引起皮肤表皮中的细胞凋亡，导致屏障的破坏。以前，我们已经证明BNIP3刺激表皮角质形成细胞中的自噬，并在UVB照射后对这些细胞具有保护作用。在这项研究中，我们发现，活性氧（ROS）的积累，UVB照射足以触发激活JNK和ERK丝裂原活化蛋白激酶（MAPK）在人原代表皮角质形成细胞。反过来，激活的JNK和ERK MAPK介导BNIP3表达的上调。用抗氧化剂或MAPK的特异性抑制剂U0126和JNK抑制剂处理显著减弱了由UVB触发的BNIP3的表达，随后通过凋亡诱导细胞死亡。此外，UVB诱导的细胞凋亡显着刺激氯喹或巴弗洛霉素A1，自噬抑制剂。此外，BNIP3是UVB照射后功能失调的线粒体降解所必需的。这些数据清楚地表明，BNIP3诱导的自噬，这是通过UVB产生的ROS介导的JNK和ERK MAPK激活发生的，在保护皮肤表皮免受UVB照射中具有至关重要的作用。
The human skin has an important role in barrier function. Ultraviolet rays (UV) from sunlight exposure can cause cell apoptosis in the skin epidermis, resulting in the disruption of the barrier. Previously, we have demonstrated that BNIP3 stimulates autophagy in epidermal keratinocytes and has a protective effect in these cells upon UVB irradiation. In this study, we found that the accumulation of reactive oxygen species (ROS) by UVB irradiation was sufficient to trigger the activation of JNK and ERK mitogen-activated protein kinase (MAPK) in human primary epidermal keratinocytes. In turn, activated JNK and ERK MAPK mediated the upregulation of BNIP3 expression. Treatment with an antioxidant reagent or a specific inhibitor of MAPK, U0126, and a JNK inhibitor significantly attenuated the expression of BNIP3 triggered by UVB, followed by the induction of cell death by apoptosis. Furthermore, UVB-induced apoptosis was significantly stimulated by chloroquine or bafilomycin A1, an inhibitor of autophagy. Moreover, BNIP3 was required for the degradation of dysfunctional mitochondria upon UVB irradiation. These data clearly indicated that BNIP3-induced autophagy, which occurs via UVB-generated ROS-mediated JNK and ERK MAPK activation, has a crucial role in the protection of the skin epidermis against UVB irradiation.