title: Pathogenic connexin-31 forms constitutively active hemichannels to promote necrotic cell death.
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.
authors.affiliation: The State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha, Hunan, China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Chi
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Mujun
authors.initials: M
authors.lastname: Liu
authors.forename: Jieqiong
authors.initials: J
authors.lastname: Tan
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Tang
authors.forename: Qian
authors.initials: Q
authors.lastname: Pan
authors.forename: Danling
authors.initials: D
authors.lastname: Wang
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D016923:Cell Death; D002460:Cell Line; D017630:Connexins / Q000235:genetics* / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D056266:Erythrokeratodermia Variabilis / Q000235:genetics; D017629:Gap Junctions; D006367:HeLa Cells; D006801:Humans; D007118:Immunoassay / Q000379:methods; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009154:Mutation; D009336:Necrosis; D010641:Phenotype; D017382:Reactive Oxygen Species
chemical_list: D017630:Connexins; D017382:Reactive Oxygen Species; C068044:GJB3 protein, human; D000255:Adenosine Triphosphate