Pathogenic Connexin-31 Forms Constitutively Active Hemichannels to Promote Necrotic Cell Death
Pathogenic Connexin-31 Forms Constitutively Active Hemichannels to Promote Necrotic Cell Death
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致病性 Connexin-31 形成持续活跃的半通道以促进坏死细胞死亡
DOI：
10.1371/journal.pone.0032531
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发表时间：
2012-02-29
期刊：
影响因子：
3.7
通讯作者：
Zhang, Zhuohua
中科院分区：
文献类型：
--
作者：
Chi, Jingwei;Li, Li;Zhang, Zhuohua
连接蛋白-31（Cx 31）的突变与多种人类疾病相关，包括可变性红斑角皮病（EKV）。Cx 31致病性突变体的分子作用仍然很大程度上难以捉摸。我们在这里报告EKV致病突变体Cx 31 R42 P的表达诱导细胞死亡与坏死的特点。连接蛋白半通道抑制剂或高细胞外钙抑制半通道活性可抑制Cx 31 R42 P诱导的细胞死亡。Cx 31 R42 P的表达诱导ER应激，导致活性氧（ROS）产生，进而调节Cx 31 R42 P半通道的门控和Cx 31 R42 P诱导的细胞死亡。此外，Cx 31 R42 P半通道在介导细胞ATP释放中起重要作用。相反，用表达野生型Cx 31的细胞未检测到半通道活性。总之，结果表明，Cx 31 R42 P形成组成型活性半通道，以促进坏死细胞死亡。Cx 31 R42 P活性半通道可能是由ER应激介导的ROS过度产生引起的。本研究揭示了Cx 31突变体诱导EKV的发病机制，为EKV的治疗提供了新的思路。
Mutations in Connexin-31 (Cx31) are associated with multiple human diseases including erythrokeratodermia variabilis (EKV). The molecular action of Cx31 pathogenic mutants remains largely elusive. We report here that expression of EKV pathogenic mutant Cx31R42P induces cell death with necrotic characteristics. Inhibition of hemichannel activity by a connexin hemichannel inhibitor or high extracellular calcium suppresses Cx31R42P-induced cell death. Expression of Cx31R42P induces ER stress resulting in reactive oxygen species (ROS) production, in turn, to regulate gating of Cx31R42P hemichannels and Cx31R42P induced cell death. Moreover, Cx31R42P hemichannels play an important role in mediating ATP release from the cell. In contrast, no hemichannel activity was detected with cells expressing wildtype Cx31. Together, the results suggest that Cx31R42P forms constitutively active hemichannels to promote necrotic cell death. The Cx31R42P active hemichannels are likely resulted by an ER stress mediated ROS overproduction. The study identifies a mechanism of EKV pathogenesis induced by a Cx31 mutant and provides a new avenue for potential treatment strategy of the disease.