Pathogenic connexin-31 forms constitutively active hemichannels to promote necrotic cell death

Jingwei Chi, Li Na Li, Mu Jun Liu, Jie Qiong Tan, Chengyuan Tang, Qian Pan, Danling Wang, Zhuohua Zhang

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    25 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Article numbere32531
    Pages (from-to)e32531
    Number of pages9
    JournalPLoS One
    Volume7
    Issue number2
    DOIs
    Publication statusPublished - 2012

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  • Cite this

    Chi, J., Li, L. N., Liu, M. J., Tan, J. Q., Tang, C., Pan, Q., Wang, D., & Zhang, Z. (2012). Pathogenic connexin-31 forms constitutively active hemichannels to promote necrotic cell death. PLoS One, 7(2), e32531. [e32531]. https://doi.org/10.1371/journal.pone.0032531